5-hydroxytryptamine receptor 7 modulators and their use as therapeutic agents

ABSTRACT

Pharmaceutical compositions of the invention comprise functionalized lactone derivatives having a disease-modifying action in the treatment of diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application62/474,280, filed Mar. 21, 2017, which is incorporated by reference inits entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under grant numberHHSN-271-2008-00025-C awarded by the National Institute of MentalHealth. The government has certain rights in the invention.

FIELD OF INVENTION

Embodiments of the invention are directed to novel compounds useful asmodulators of 5-hydroxytryptamine receptor 7 (5-HT₇) activity and theirmethod of use. Embodiments are further directed to a novel chemotypeuseful for the treatment diseases that are associated with dysregulationof 5-hydroxytryptamine receptor 7 activity.

BACKGROUND OF THE INVENTION

Serotonin was discovered in the late 1940s and is present in both theperipheral and central nervous systems [Physiol. Res, 60 (2011) 15-25;Psychopharmacology 213 (2011) 167-169]. Serotonin or 5-hydroxytryptamine(5-HT) is a monoamine neurotransmitter of the indolalkylamine group thatacts at synapses of nerve cells. Seven distinct families of serotoninreceptors have been identified and at least 20 subpopulations have beencloned on the basis of sequence similarity, signal transduction couplingand pharmacological characteristics. The seven families of 5-HT receptorare named 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆, and 5-HT₇ and eachof these receptors in turn has subfamilies or subpopulations. The signaltransduction mechanism for all seven families have been studied and itis known that activation of 5-HT₁ and 5-HT₅ receptors causes a decreasein intracellular cAMP whereas activation of 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆,and 5-HT₇ results in an increase in intracellular TP3 and DAG. The 5-HTpathways in the brain are important targets for drug development in thearea of CNS disorders. The neurotransmitter binds to its a G-proteincoupled receptor and is involved in a wide variety of actions includingcognition, mood, anxiety, attention, appetite, cardiovascular function,vasoconstriction, sleep (ACS Medicinal Chemistry Letters, 2011, 2,929-932; Physiological Research, 2011, 60, 15-25), inflammatory boweldisease (IBD), and intestinal inflammation (WO 2012058769, Khan, W. I.,et. al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizuredisorders (Epilepsy Research (2007) 75, 39), drug addiction, and alcoholaddiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8,1-9) among others.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward novel 5-hydroxytryptaminereceptor 7 (5-HT7) activity modulators, compounds of formula (I),

including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein:

n is 1, 2, or 3;

R^(1a) and R^(1b) are each independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, and C₁₋₆ branched alkyl, orRia and R^(1b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms;

R² is selected from a group consisting of a benzene ring that isoptionally substituted with 0 to 3 R³ groups that are not hydrogen, a3-pyridine ring that is optionally substituted with 0 to 2 R⁴ groupsthat are not hydrogen, and a 2-pyridine ring that is optionallysubstituted with 0 to 2 R⁴ groups that are not hydrogen;

R³ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶,CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b);

the terms R^(3a), R^(3b), R^(3c), R^(3d), and R^(3e) may be used todesignate individual R³ groups on a benzene ring;

R⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶,CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b); the terms R^(4a), R^(4b),R^(4c), and R^(4d) may be used to designate individual R⁴ groups on apyridine ring;

R⁵ is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R⁶ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(7a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(7b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8a) and R^(8b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms optionally containingan oxygen;

R⁹ is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R¹⁰ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(11a) is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl; and

R^(11b) is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl.

The present invention further relates to compositions comprising: aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing diseases that involve dysregulation of 5-hydroxytryptaminereceptor 7 activity, including, for example, circadian rhythm disorder,depression, schizophrenia, neurogenic inflammation, hypertension,peripheral, vascular diseases, migraine, neuropathic pain, peripheralpain, allodynia, thermoregulation disorder, learning disorder, memorydisorder, hippocampal signaling disorder, sleep disorder, attentiondeficit/hyperactivity disorder, anxiety, avoidant personality disorder,premature ejaculation, eating disorder, premenstrual syndrome,premenstrual dysphonic disorder, seasonal affective disorder, bipolardisorder, inflammatory bowel disease (IBD), intestinal inflammation,epilepsy, seizure disorders, drug addiction, and alcohol addiction saidmethod comprising administering to a subject an effective amount of acompound or composition according to the present invention.

The present invention yet further relates to a method for treating orpreventing diseases that involve dysregulation of 5-hydroxytryptaminereceptor 7 activity, including, for example, circadian rhythm disorder,depression, schizophrenia, neurogenic inflammation, hypertension,peripheral, vascular diseases, migraine, neuropathic pain, peripheralpain, allodynia, thermoregulation disorder, learning disorder, memorydisorder, hippocampal signaling disorder, sleep disorder, attentiondeficit/hyperactivity disorder, anxiety, avoidant personality disorder,premature ejaculation, eating disorder, premenstrual syndrome,premenstrual dysphonic disorder, seasonal affective disorder, bipolar,disorder inflammatory bowel disease (IBD), intestinal inflammation,epilepsy, seizure disorders, drug addiction, and alcohol addictionwherein said method comprises administering to a subject a compositioncomprising an effective amount of one or more compounds according to thepresent invention and an excipient.

The present invention also relates to a method for treating orpreventing diseases or conditions associated with circadian rhythmdisorder, depression, schizophrenia, neurogenic inflammation,hypertension, peripheral, vascular diseases, migraine, neuropathic pain,peripheral pain, allodynia, thermoregulation disorder, learningdisorder, memory disorder, hippocampal signaling disorder, sleepdisorder, attention deficit/hyperactivity disorder, anxiety, avoidantpersonality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, bipolar disorder, inflammatory bowel disease (IBD),intestinal inflammation, epilepsy, seizure disorders, drug addiction,alcohol addiction and diseases that involve dysregulation of5-hydroxytryptamine receptor 7 activity. Said methods compriseadministering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing diseases or conditions associated with circadian rhythmdisorder, depression, schizophrenia, neurogenic inflammation,hypertension, peripheral, vascular diseases, migraine, neuropathic pain,peripheral pain, allodynia, thermoregulation disorder, learningdisorder, memory disorder, hippocampal signaling disorder, sleepdisorder, attention deficit/hyperactivity disorder, anxiety, avoidantpersonality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, and bipolar disorder, inflammatory bowel disease(IBD), intestinal inflammation, epilepsy, seizure disorders, drugaddiction, alcohol addiction and diseases that involve dysregulation of5-hydroxytryptamine receptor 7 activity, wherein said method comprisesadministering to a subject a composition comprising an effective amountof one or more compounds according to the present invention and anexcipient.

The present invention also relates to a method for treating orpreventing diseases or conditions associated with dysregulation of5-hydroxytryptamine receptor 7 activity. Said methods compriseadministering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing diseases or conditions associated with dysregulation of5-hydroxytryptamine receptor 7 activity, wherein said method comprisesadministering to a subject a composition comprising an effective amountof one or more compounds according to the present invention and anexcipient.

The present invention further relates to a process for preparing the5-hydroxytryptamine receptor 7 activity modulators of the presentinvention.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

There is evidence that suggests a role for the 5-HT₇ receptor in anumber of medical disorders. 5-HT₇ receptor activity modulators arelikely to have a beneficial effect on patients suffering from thesedisorders. The disorders in which 5-HT₇ dysregulation plays a role andmodulation of 5-HT₇ receptor activity by a therapeutic agent may be aviable approach to therapeutic relief include, but are not limited to,circadian rhythm disorder, depression, schizophrenia, neurogenicinflammation, hypertension, peripheral, vascular diseases, migraine(Vanhoenacker, P. et al. Trends in Pharmacological Sciences, 2000, 21,2, 70-77), neuropathic pain, peripheral pain, allodynia (EP1875899),thermoregulation disorder, learning disorder, memory disorder,hippocampal signaling disorder, sleep disorder (WO20100197700) attentiondeficit/hyperactivity disorder (ADHD) (WO20100069390), anxiety, avoidantpersonality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, bipolar disorder (WO20040229874), inflammatory boweldisease (IBD), intestinal inflammation (WO 2012058769, Khan, W. I., et.al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizuredisorders (Epilepsy Research (2007) 75, 39), drug addiction, and alcoholaddiction (Hauser, S. R. et. al. Frontiers in Neuroscience. 2015, 8,1-9).

There is a long felt need for new 5-HT₇ modulators that will providetherapeutic relief from patients suffering from diseases associated withdysregulation of 5-hydroxytryptamine receptor 7 activity. The inventionaddresses the need to identify novel 5-HT₇ modulators capable oftreating disease associated with dysregulation of 5-hydroxytryptaminereceptor 7 activity. The present invention addresses the need to developnew therapeutic agents for the treatment and prevention of circadianrhythm disorder, depression, schizophrenia, neurogenic inflammation,hypertension, peripheral, vascular diseases, migraine, neuropathic pain,peripheral pain, allodynia, thermoregulation disorder, learningdisorder, memory disorder, hippocampal signaling disorder, sleepdisorder, attention deficit/hyperactivity disorder, anxiety, avoidantpersonality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, bipolar disorder, inflammatory bowel disease (IBD),intestinal inflammation epilepsy, seizure disorders, drug addiction, andalcohol addiction.

The 5-hydroxytryptamine receptor 7 activity modulators of the presentinvention are capable of treating and preventing diseases associatedwith dysregulation of 5-hydroxytryptamine receptor 7 activity, forexample circadian rhythm disorder, depression, schizophrenia, neurogenicinflammation, hypertension, peripheral, vascular diseases, migraine,neuropathic pain, peripheral pain, allodynia, thermoregulation disorder,learning disorder, memory disorder, hippocampal signaling disorder,sleep disorder, attention deficit/hyperactivity disorder, anxiety,avoidant personality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, bipolar disorder, inflammatory bowel disease (IBD),intestinal inflammation, epilepsy, seizure disorders, drug addiction,and alcohol addiction. It has been discovered that the5-hydroxytryptamine receptor 7 play a role in a number of medicaldisorders, and therefore, 5-HT₇ receptor activity modulators are likelyto have a beneficial effect on patients suffering from these disorders.The disorders in which 5-HT₇ dysregulation plays a role and modulationof 5-HT₇ receptor activity by a therapeutic agent may be a viableapproach to therapeutic relief include, but are not limited to,circadian rhythm disorder, depression, schizophrenia, neurogenicinflammation, hypertension, peripheral, vascular diseases, migraine(Vanhoenacker, P. et. al. Trends in Pharmacological Sciences, 2000, 21,2, 70-77), neuropathic pain, peripheral pain, allodynia (EP1875899),thermoregulation disorder, learning disorder, memory disorder,hippocampal signaling disorder, sleep disorder (WO20100197700) attentiondeficit/hyperactivity disorder (ADHD) (WO20100069390), anxiety, avoidantpersonality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, bipolar disorder (WO20040229874), inflammatory boweldisease (IBD), intestinal inflammation (WO 2012058769) epilepsy, seizuredisorders (Epilepsy Research (2007) 75, 39), drug addiction, and alcoholaddiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8,1-9).

Without wishing to be limited by theory, it is believed that5-hydroxytryptamine receptor 7 receptor activity modulators of thepresent invention can ameliorate, abate, otherwise cause to becontrolled, diseases associated with dysregulation of5-hydroxytryptamine receptor 7 activity. The diseases include, but arenot limited to circadian rhythm disorder, depression, schizophrenia,neurogenic inflammation, hypertension, peripheral, vascular diseases,migraine, neuropathic pain, peripheral pain, allodynia, thermoregulationdisorder, learning disorder, memory disorder, hippocampal signalingdisorder, sleep disorder, attention deficit/hyperactivity disorder,anxiety, avoidant personality disorder, premature ejaculation, eatingdisorder, premenstrual syndrome, premenstrual dysphonic disorder,seasonal affective disorder, bipolar disorder, inflammatory boweldisease (IBD), intestinal inflammation, epilepsy, seizure disorders,drug addiction, and alcohol addiction.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings also consistessentially of, or consist of, the recited components, and that theprocesses of the present teachings also consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from a groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously.

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and/or “aliphatic”whether used alone or as part of a substituent group refers to straightand branched carbon chains having 1 to 20 carbon atoms or any numberwithin this range, for example 1 to 6 carbon atoms or 1 to 4 carbonatoms. Designated numbers of carbon atoms (e.g. C₁₋₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groupscan be optionally substituted. Non-limiting examples of substitutedalkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl,aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl,3-carboxypropyl, and the like. In substituent groups with multiple alkylgroups such as (C₁₋₆alkyl)₂amino, the alkyl groups may be the same ordifferent.

As used herein, the terms “alkenyl” and “alkynyl” groups, whether usedalone or as part of a substituent group, refer to straight and branchedcarbon chains having 2 or more carbon atoms, preferably 2 to 20, whereinan alkenyl chain has at least one double bond in the chain and analkynyl chain has at least one triple bond in the chain. Alkenyl andalkynyl groups can be optionally substituted. Nonlimiting examples ofalkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, andthe like. Nonlimiting examples of substituted alkenyl groups include2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl,7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl,and the like. Nonlimiting examples of alkynyl groups include ethynyl,prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.Nonlimiting examples of substituted alkynyl groups include,5-hydroxy-5-methylhex-3-ynyl. 6-hydroxy-6-methylhept-3-yn-2-yl,5-hydroxy-5-ethylhept-3-ynyl, and the like.

As used herein, “cycloalkyl,” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused,bridged, and/or spiro ring systems), wherein the carbon atoms arelocated inside or outside of the ring system. Any suitable ring positionof the cycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutvl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl,decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens of an alkyl grouphave been replaced with halogens (e.g., —CF₃, —CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substituents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm C₃-C₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atomsand at least one oxygen atom (e.g., tetrahydrofuran,tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may besubstituted.

The term “haloalkoxy” refers to the group —O-haloalkyl, wherein thehaloalkyl group is as defined above. Examples of haloalkoxy groupsinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, and pentafluoroethoxyl.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group-alkyl-aryl, wherethe alkyl and aryl groups are as defined herein. Aralkyl groups of thepresent invention are optionally substituted. Examples of arylalkylgroups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl,isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl,hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole,and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclicunits having 2 or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. Heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl,oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl,pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limitingexamples of heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthvridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, 1H-benzo[d]imidazol-2(3H)-onyl,1H-benzo[d]imidazolyl, and isoquinolinyl.

One non-limiting example of a heteroaryl group as described above isC₁-C₅ heteroaryl, which has 1 to 5 carbon ring atoms and at least oneadditional ring atom that is a heteroatom (preferably 1 to 4 additionalring atoms that are heteroatoms) independently selected from nitrogen(N), oxygen (O), or sulfur (S). Examples of C₁-C₅ heteroaryl include,but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl,imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl,furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., I to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted.

For the purposed of the present invention fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be considered to belong to the cyclic familycorresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclicunit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms of asingle moiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. The term “substituted” is used throughout thepresent specification to indicate that a moiety can have one or more ofthe hydrogen atoms replaced by a substituent. When a moiety is describedas “substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl,cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groupsdefined herein, whether used alone or as part of another group, can beoptionally substituted. Optionally substituted groups will be soindicated.

The following are non-limiting examples of substituents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine (I)), —CN, —NO₂, oxo (═O), —OR¹²,—SR¹², —N(R¹²)₂, —NR¹²C(O)R¹², —SO₂R¹², —SO₂OR¹², —SO₂N(R¹²)₂, —C(O)R¹²,—C(O)OR¹², —C(O)N(R¹)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, orheteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN, —NO₂, oxo, and R¹²; wherein R¹², ateach occurrence, independently is hydrogen, —OR¹², —SR¹², —C(O)R¹³,—C(O)OR¹³, —C(O)N(R¹³)₂, —SO₂R¹³, —S(O)₂OR¹³, —N(R¹³)₂, —NR¹³C(O)R¹³,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl(e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R¹²units taken together with the atom(s) to which they are bound form anoptionally substituted carbocycle or heterocycle wherein said carbocycleor heterocycle has 3 to 7 ring atoms; wherein R¹³, at each occurrence,independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, orheteroaryl, or two R¹³ units taken together with the atom(s) to whichthey are bound form an optionally substituted carbocycle or heterocyclewherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

-   -   i) —OR¹⁴; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;    -   ii) —C(O)R¹⁴; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;    -   iii) —C(O)OR¹⁴; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;    -   iv) —C(O)N(R¹⁴)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;    -   v) —N(R)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);    -   vi) halogen: —F, —Cl, —Br, and —I;    -   vii) —CH_(e)X; wherein X is halogen, m is from 0 to 2, e+g=3;        for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   viii) —SO₂R¹⁴; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;    -   ix) C₁-C₆ linear, branched, or cyclic alkyl;    -   x) Cyano    -   xi) Nitro;    -   xii) N(R¹⁴)C(O)R¹⁴;    -   xiii) Oxo (═O);    -   xiv) Heterocycle; and    -   xv) Heteroaryl.        wherein each R¹⁴ is independently hydrogen, optionally        substituted C₁-C₆ linear or branched alkyl (e.g., optionally        substituted C₁-C₄ linear or branched alkyl), or optionally        substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄        cycloalkyl); or two R¹⁴ units can be taken together to form a        ring comprising 3-7 ring atoms. In certain aspects, each R¹⁴ is        independently hydrogen, C₁-C₆ linear or branched alkyl        optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆        cycloalkyl.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually discloseC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C2-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C4-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,”“analog,” and “composition of matter” stand equally well for the5-hydroxytryptamine receptor 7 activity modulators described herein,including all enantiomeric forms, diastereomeric forms, salts, and thelike, and the terms “compound,” “analog,” and “composition of matter”are used interchangeably throughout the present specification.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastereomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with morpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄,Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, whena compound disclosed herein contains a basic moiety, salts can be formedusing organic and inorganic acids. For example, salts can be formed fromthe following acids: acetic, propionic, lactic, benzenesulfonic,benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic,ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic,mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g., in N(R⁹)₂, each R⁹ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The terms “treat” and “treating” and “treatment” as used herein, referto partially or completely alleviating, inhibiting, ameliorating and/orrelieving a condition from which a patient is suspected to suffer.

As used herein. “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention.

The 5-Hydroxytryptamine Receptor 7 Activity Modulators

The 5-hydroxytryptamine receptor 7 activity modulators of the presentinvention include all enantiomeric and diastereomeric forms alts thereofhaving the formula

including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein:including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein:

n is 1, 2, or 3;

R^(1a) and R^(1b) are each independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, and C₁₋₆ branched alkyl, orR^(1a) and R^(1b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms;

R² is selected from a group consisting of a benzene ring that isoptionally substituted with 0 to 3 R³ groups that are not hydrogen, a3-pyridine ring that is optionally substituted with 0 to 2 R⁴ groupsthat are not hydrogen, and a 2-pyridine ring that is optionallysubstituted with 0 to 2 R⁴ groups that are not hydrogen;

R³ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶,CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b);

the terms R^(3a), R^(3b), R^(3c), R^(3d), and R^(3e) may be used todesignate individual R³ groups on a benzene ring;

R⁴ is at each occurrence independently selected from the groupconsisting of hydrogen, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branchedalkoxy, C₃₋₇ cycloalkoxy, C₁-6 linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶,CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b);

the terms R^(4a), R⁴, R^(4c), and R^(4d) may be used to designateindividual R⁴ groups on a pyridine ring;

R⁵ is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R⁶ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(7a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(7b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8a) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8b) is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(8a) and R^(8b) may be taken together with the atom to which they arebound to form a ring having from 3 to 7 ring atoms optionally containingan oxygen;

R⁹ is at each occurrence independently selected from the groupconsisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R¹⁰ is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl;

R^(11a) is at each occurrence independently selected from the groupconsisting of hydrogen, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl; and

R^(11b) is at each occurrence independently selected from the groupconsisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇cycloalkyl.

In one embodiment, the present invention includes compounds havingformula (IIa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

-   -   at least 2 of the group R^(3a), R^(3b), R^(3c), R^(3d), and        R^(3e) are hydrogen and 0 to 3 of R^(3a), R^(3b), R^(3c),        R^(3d), and R^(3e) are independently selected from the group        consisting of OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇        branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃,        branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇        branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl,        —S(C₁₋₆ linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇        cycloalkyl), —SO₂(C₁₋₆ linear alkyl), SO₂(C₃₋₇ branched alkyl),        —SO₂(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶, CONR^(7a)R^(7b),        SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and        NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (IIb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

-   -   at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are        hydrogen and 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are        independently selected from the group consisting of OH, NO₂,        halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇        cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇        cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl,        C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁-6 linear alkyl),        S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear        alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵,        CO₂R⁶, CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b),        NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (IIc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are hydrogenand 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy. C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶,CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (III):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (IIIa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(3a), R^(3b), R^(3c), R^(3d), and R^(3e) arehydrogen and 0 to 3 of R^(3a), R^(3b), R^(3c), R^(3d), and R^(3c) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR³,CO₂R⁶, CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (IIIb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are hydrogenand 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶,CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (IIIc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

-   -   at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are        hydrogen and 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are        independently selected from the group consisting of OH, NO₂,        halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇        cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇        cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl,        C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),        S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear        alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C3-, cycloalkyl), COR⁵,        CO₂R⁶, CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b),        NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (IV):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (IVa):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(3a), R^(3b), R^(3c), R^(3d), and R^(3e) arehydrogen and 0 to 3 of R^(3a), R^(3b), R^(3c), R^(3d), and R^(3e) areindependently selected from the group consisting of OH, NO₂, halogen,CN, C₁₋₆ linear alkyl, C3- branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linearalkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl,C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl),—SO₂(C-(linear alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇, cycloalkyl),COR⁵, CO₂R⁶, CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b),NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (IVb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

-   -   at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are        hydrogen and 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are        independently selected from the group consisting of OH, NO₂,        halogen, CN, C₁₋₆ linear alkyl, C₃₋₇, branched alkyl, C₃₋₇        cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇        cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl,        C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),        S(C₃₋₇ branched alkyl). —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear        alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵,        CO₂R⁶, CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b),        NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (IVc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are hydrogenand 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are independentlyselected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linearalkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branchedhaloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear alkyl),SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶,CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹,NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (V):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof.

In one embodiment, the present invention includes compounds havingformula (Va):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

-   -   at least 2 of the group R^(3a), R^(3b), R^(3c), R^(3d), and        R^(3e) are hydrogen and 0 to 3 of R^(3a), R^(3b), R^(3c),        R^(3d), and R^(3e) are independently selected from the group        consisting of OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇        branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇        branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇        branched haloalkyl, C₁₋₆ linear haloalkoxy, heterocyclyl,        —S(C₁₋₆ linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇        cycloalkyl), —SO₂(C₁₋₆ linear alkyl), SO₂(C₃₋₇ branched alkyl),        —SO₂(C₃₋₇ cycloalkyl), COR⁵, CO₂R⁶, CONR^(7a)R^(7b),        SO₂NR^(7a)R^(7b), NR^(8a)R^(8b), NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and        NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (Vb):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

-   -   at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are        hydrogen and 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are        independently selected from the group consisting of OH, NO₂,        halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇        cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇        cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl,        C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),        S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear        alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵,        CO₂R⁶, CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b),        NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In one embodiment, the present invention includes compounds havingformula (Vc):

Including hydrates, solvates, enantiomers, diastereomers,pharmaceutically acceptable salts, and complexes thereof wherein:

-   -   at least 2 of the group R^(4a), R^(4b), R^(4c), and R^(4d), are        hydrogen and 0 to 2 of R^(4a), R^(4b), R^(4c), and R^(4d) are        independently selected from the group consisting of OH, NO₂,        halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇        cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇        cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl,        C₁₋₆ linear haloalkoxy, heterocyclyl, —S(C₁₋₆ linear alkyl),        S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), —SO₂(C₁₋₆ linear        alkyl), SO₂(C₃₋₇ branched alkyl), —SO₂(C₃₋₇ cycloalkyl), COR⁵,        CO₂R⁶, CONR^(7a)R^(7b), SO₂NR^(7a)R^(7b), NR^(8a)R^(8b),        NR^(8a)COR⁹, NR^(8a)SO₂R¹⁰, and NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments n is 1.

In some embodiments n is 2.

In some embodiments n is 3.

In some embodiments R^(1a) is hydrogen.

In some embodiments R^(1a) is C₁₋₆ linear alkyl.

In some embodiments R^(1a) is C₁₋₆ branched alkyl.

In some embodiments R^(1b) is hydrogen.

In some embodiments R^(1b) is C₁₋₆ linear alkyl.

In some embodiments R^(1b) is C₁₋₆ branched alkyl.

In some embodiments R^(1a) and R^(1b) are taken together with the atomto which they are bound to form a ring having from 3 ring atoms.

In some embodiments R^(1a) and R^(1b) are taken together with the atomto which they are bound to form a ring having from 4 ring atoms.

In some embodiments R^(1a) and R^(1b) are taken together with the atomto which they are bound to form a ring having from 5 ring atoms.

In some embodiments R^(1a) and R^(1b) are taken together with the atomto which they are bound to form a ring having from 6 ring atoms.

In some embodiments R^(1a) and R^(1b) are taken together with the atomto which they are bound to form a ring having from 7 ring atoms.

In some embodiments R² is a benzene ring that is optionally substitutedwith 0 to 3 R³ groups that are not hydrogen.

In some embodiments R² is a 3-pyridine ring that is optionallysubstituted with 0 to 2 R⁴ groups that are not hydrogen.

In some embodiments R² is a 2-pyridine ring that is optionallysubstituted with 0 to 2 R⁴ groups that are not hydrogen.

In some embodiments R³ is hydrogen.

In some embodiments R³ is OH.

In some embodiments R³ is NO₂.

In some embodiments R³ is halogen.

In some embodiments R³ is CN.

In some embodiments R³ is C₁₋₆ linear alkyl.

In some embodiments R³ is C₃₋₇ branched alkyl,

In some embodiments R³ is C₃₋₇ cycloalkyl.

In some embodiments R³ is C₁₋₆ linear alkoxy.

In some embodiments R³ is C₃₋₇ branched alkoxy.

In some embodiments R³ is C₃₋₇ cycloalkoxy.

In some embodiments R³ is C₁₋₆ linear haloalkyl.

In some embodiments R³ is C₃₋₇ branched haloalkyl.

In some embodiments R³ is C₁₋₆ linear haloalkoxy,

In some embodiments R³ is —S(C₁₋₆ linear alkyl),

In some embodiments R³ is —S(C₃₋₇ branched alkyl),

In some embodiments R³ is —S(C₃₋₇ cycloalkyl).

In some embodiments R³ is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R³ is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R³ is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R³ is COR.

In some embodiments R³ is CO₂R⁶.

In some embodiments R³ is CONR^(7a)R^(7b).

In some embodiments R³ is SO₂NR^(7a)R^(7b).

In some embodiments R³ is NR^(8a)R^(8b).

In some embodiments R³ is NR^(8a)COR⁹.

In some embodiments R³ is NR^(8a)SO₂R¹⁰.

In some embodiments R³ is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(3a) is hydrogen.

In some embodiments R^(3a) is OH.

In some embodiments R^(3a) is NO₂.

In some embodiments R^(3a) is halogen.

In some embodiments R^(3a) is CN.

In some embodiments R^(3a) is C₁₋₆ linear alkyl.

In some embodiments R^(3a) is C₃₋₇ branched alkyl,

In some embodiments R^(3a) is C₃₋₇ cycloalkyl.

In some embodiments R^(3a) is C₁₋₆ linear alkoxy.

In some embodiments R^(3a) is C₃₋₇ branched alkoxy.

In some embodiments R^(3a) is C₃₋₇ cycloalkoxy.

In some embodiments R^(3a) is C₁₋₆ linear haloalkyl.

In some embodiments R^(3a) is C₃₋₇ branched haloalkyl.

In some embodiments R^(3a) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(3a) is heterocyclyl.

In some embodiments R^(3a) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(3a) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(3a) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(3a) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(3a) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(3a) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(3a) is COR⁵.

In some embodiments R^(3a) is CO₂R⁶.

In some embodiments R^(3a) is CONR^(7a)R^(7b).

In some embodiments R^(3a) is SO₂NR^(7a)R^(7b).

In some embodiments R^(3a) is NR^(8a)R^(8b).

In some embodiments R^(3a) is NR^(8a)COR⁹.

In some embodiments R^(3a) is NR^(8a)SO₂R¹.

In some embodiments R^(3a) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(3b) is hydrogen.

In some embodiments R^(3b) is OH.

In some embodiments R^(3b) is NO₂.

In some embodiments R^(3b) is halogen.

In some embodiments R^(3b) is CN.

In some embodiments R^(3b) is C₁₋₆ linear alkyl.

In some embodiments R^(3b) is C₃₋₇ branched alkyl,

In some embodiments R^(3b) is C₃₋₇ cycloalkyl.

In some embodiments R^(3b) is C₁₋₆ linear alkoxy.

In some embodiments R^(3b) is C₃₋₇ branched alkoxy.

In some embodiments R^(3b) is C₃₋₇ cycloalkoxy.

In some embodiments R^(3b) is C₁₋₆ linear haloalkyl.

In some embodiments R^(3b) is C₃₋₇ branched haloalkyl.

In some embodiments R^(3b) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(3b) is heterocyclyl.

In some embodiments R^(3b) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(3b) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(3b) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(3b) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(3b) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(3b) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(3b) is COR⁵.

In some embodiments R^(3b) is CO₂R⁶.

In some embodiments R^(3b) is CONR^(7a)R^(7b).

In some embodiments R^(3b) is SO₂NR^(7a)R^(7b),

In some embodiments R^(3b) is NR^(8a)R^(8b).

In some embodiments R^(3b) is NR^(8a)COR⁹.

In some embodiments R^(3b) is NR^(8a)SO₂R¹⁰.

In some embodiments R^(3b) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(3c) is hydrogen.

In some embodiments R^(3c) is OH.

In some embodiments R^(3c) is NO₂.

In some embodiments R^(3c) is halogen.

In some embodiments R^(3c) is CN.

In some embodiments R^(3c) is C₁₋₆ linear alkyl.

In some embodiments R^(3c) is C₃₋₇ branched alkyl,

In some embodiments R^(3c) is C₃₋₇ cycloalkyl.

In some embodiments R^(3c) is C₁₋₆ linear alkoxy.

In some embodiments R^(3c) is C₃₋₇ branched alkoxy.

In some embodiments R^(3c) is C₃₋₇ cycloalkoxy.

In some embodiments R^(3c) is C₁₋₆ linear haloalkyl.

In some embodiments R^(3c) is C₃₋₇ branched haloalkyl.

In some embodiments R^(3c) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(3c) is heterocyclyl.

In some embodiments R^(3c) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(3c) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(3c) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(3c) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(3c) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(3c) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(3c) is COR⁵.

In some embodiments R^(3c) is CO₂R⁶.

In some embodiments R^(3c) is CONR^(7a)R^(7b).

In some embodiments R^(3c) is SO₂NR^(7a)R^(7b),

In some embodiments R^(3c) is NR^(8a)R^(8b).

In some embodiments R^(3c) is NR^(8a)COR⁹.

In some embodiments R^(3c) is NR^(8a)SO₂R¹⁰.

In some embodiments R^(3c) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(3d) is hydrogen.

In some embodiments R^(3d) is OH.

In some embodiments R^(3d) is NO₂.

In some embodiments R^(3d) is halogen.

In some embodiments R^(3d) is CN.

In some embodiments R^(3d) is C₁₋₆ linear alkyl.

In some embodiments R^(3d) is C₃₋₇ branched alkyl,

In some embodiments R^(3d) is C₃₋₇ cycloalkyl.

In some embodiments R^(3d) is C₁₋₆ linear alkoxy.

In some embodiments R^(3d) is C₃₋₇ branched alkoxy.

In some embodiments R^(3d) is C₃₋₇ cycloalkoxy.

In some embodiments R^(3d) is C₁₋₆ linear haloalkyl.

In some embodiments R^(3d) is C₃₋₇ branched haloalkyl.

In some embodiments R^(3d) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(3d) is heterocyclyl.

In some embodiments R^(3d) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(3d) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(3d) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(3d) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(3d) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(3d) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(3d) is COR⁵.

In some embodiments R^(3d) is CO₂R⁶.

In some embodiments R^(3d) is CONR^(7a)R^(7b).

In some embodiments R^(3d) is SO₂NR^(7a)R^(7b).

In some embodiments R^(3d) is NR^(8a)R^(8b).

In some embodiments R^(3d) is NR^(8a)COR⁹.

In some embodiments R^(3d) is NR^(8a)SO₂R¹⁰.

In some embodiments R^(3d) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(3e) is hydrogen.

In some embodiments R^(3e) is OH.

In some embodiments R^(3e) is NO₂.

In some embodiments R^(3e) is halogen.

In some embodiments R^(3e) is CN.

In some embodiments R^(3e) is C₁₋₆ linear alkyl.

In some embodiments R^(3e) is C₃₋₇ branched alkyl,

In some embodiments R^(3e) is C₃₋₇ cycloalkyl.

In some embodiments R^(3e) is C₁₋₆ linear alkoxy.

In some embodiments R^(3e) is C₃₋₇ branched alkoxy.

In some embodiments R^(3e) is C₃₋₇ cycloalkoxy.

In some embodiments R^(3e) is C₁₋₆ linear haloalkyl.

In some embodiments R^(3e) is C₃₋₇ branched haloalkyl.

In some embodiments R^(3e) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(3e) is heterocyclyl.

In some embodiments R^(3e) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(3e) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(3e) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(3e) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(3e) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(3e) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(3e) is COR⁵.

In some embodiments R^(3e) is CO₂R⁶.

In some embodiments R^(3e) is CONR^(7a)R^(7b).

In some embodiments R^(3e) is SO₂NR^(7a)R^(7b).

In some embodiments R^(3e) is NR^(8a)R^(8b).

In some embodiments R^(3e) is NR^(8a)COR⁹.

In some embodiments R^(3e) is NR^(8a)SO₂R¹⁰.

In some embodiments R^(3e) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R⁴ is hydrogen.

In some embodiments R⁴ is OH.

In some embodiments R⁴ is NO₂.

In some embodiments R⁴ is halogen.

In some embodiments R⁴ is CN.

In some embodiments R⁴ is C₁₋₆ linear alkyl.

In some embodiments R⁴ is C₃₋₇ branched alkyl.

In some embodiments R⁴ is C₃₋₇ cycloalkyl.

In some embodiments R⁴ is C₁₋₆ linear alkoxy.

In some embodiments R⁴ is C₃₋₇ branched alkoxy.

In some embodiments R⁴ is C₃₋₇ cycloalkoxy.

In some embodiments R⁴ is C₁₋₆ linear haloalkyl.

In some embodiments R⁴ is C₃₋₇ branched haloalkyl.

In some embodiments R⁴ is C₁₋₆ linear haloalkoxy,

In some embodiments R⁴ is —S(C₁₋₆ linear alkyl),

In some embodiments R⁴ is —S(C₃₋₇ branched alkyl),

In some embodiments R⁴ is —S(C₃₋₇ cycloalkyl).

In some embodiments R⁴ is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R⁴ is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R⁴ is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R⁴ is COR⁵.

In some embodiments R⁴ is CO₂R⁶.

In some embodiments R⁴ is CONR^(7a)R^(7b).

In some embodiments R⁴ is SO₂NR^(7a)R^(7b).

In some embodiments R⁴ is NR^(8a)R^(8b).

In some embodiments R⁴ is NR^(Sa)COR⁹.

In some embodiments R⁴ is NR^(8a)SO₂R¹⁰.

In some embodiments R⁴ is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(4a) is hydrogen.

In some embodiments R^(4a) is OH.

In some embodiments R^(4a) is NO₂.

In some embodiments R^(4a) is halogen.

In some embodiments R^(4a) is CN.

In some embodiments R^(4a) is C₁₋₆ linear alkyl.

In some embodiments R^(4a) is C₃₋₇ branched alkyl,

In some embodiments R^(4a) is C₃₋₇ cycloalkyl.

In some embodiments R^(4a) is C₁₋₆ linear alkoxy.

In some embodiments R^(4a) is C₃₋₇ branched alkoxy.

In some embodiments R^(4a) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4a) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4a) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4a) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(4a) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(4a) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(4a) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4a) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(4a) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(4a) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4a) is COR⁵.

In some embodiments R^(4a) is CO₂R⁶.

In some embodiments R^(4a) is CONR^(7a)R^(7b).

In some embodiments R⁴ is SO₂NR^(7a)R^(7b).

In some embodiments R^(4a) is NR^(8a)R^(8b).

In some embodiments R^(4a) is NR^(8a)COR⁹.

In some embodiments R⁴¹ is NR^(8a)SO₂R¹⁰.

In some embodiments R^(4a) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(4b) is hydrogen.

In some embodiments R^(4b) is OH.

In some embodiments R^(4b) is NO₂.

In some embodiments R^(4b) is halogen.

In some embodiments R^(4b) is CN.

In some embodiments R^(4b) is C₁₋₆ linear alkyl.

In some embodiments R^(4b) is C₃₋₇ branched alkyl,

In some embodiments R^(4b) is C₃₋₇ cycloalkyl.

In some embodiments R^(4b) is C₁₋₆ linear alkoxy.

In some embodiments R^(4b) is C₃₋₇ branched alkoxy.

In some embodiments R^(4b) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4b) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4b) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4b) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(4b) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(4b) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(4b) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4b) is —SO₂(C₁₋₆ linear alkyl).

In some embodiments R^(4b) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(4b) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4b) is COR⁵.

In some embodiments R⁴¹ is CO₂R⁶.

In some embodiments R^(4b) is CONR^(7a)R^(7b).

In some embodiments R^(4b) is SO₂NR^(7a)R^(7b).

In some embodiments R^(4b) is NR^(8a)R^(8b).

In some embodiments R^(4b) is NR^(8a)COR⁹.

In some embodiments R^(4b) is NR^(8a)SO₂R¹⁰.

In some embodiments R^(4b) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(4c) is hydrogen.

In some embodiments R^(4C) is OH.

In some embodiments R^(4c) is NO₂.

In some embodiments R^(4c) is halogen.

In some embodiments R^(4c) is CN.

In some embodiments R^(4c) is C₁₋₆ linear alkyl.

In some embodiments R^(4c) is C₃₋₇ branched alkyl,

In some embodiments R^(4c) is C₃₋₇ cycloalkyl.

In some embodiments R^(4c) is C₁₋₆ linear alkoxy.

In some embodiments R^(4c) is C₃₋₇ branched alkoxy.

In some embodiments R^(4c) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4c) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4c) is C₃₋₂ branched haloalkyl.

In some embodiments R^(4c) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(4c) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(4c) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(4c) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4c) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(4c) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(4c) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4c) is COR⁵.

In some embodiments R^(4c) is CO₂R⁶.

In some embodiments R^(4c) is CONR^(7a)R^(7b).

In some embodiments R^(4c) is SO₂NR^(7a)R^(7b),

In some embodiments R^(4c) is NR^(8a)R^(8b).

In some embodiments R^(4c) is NR^(8a)COR⁹.

In some embodiments R^(4c) is NR^(8a)SO₂R¹⁰.

In some embodiments R^(4c) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R^(4d) is hydrogen.

In some embodiments R^(4d) is OH.

In some embodiments R^(4d) is NO₂.

In some embodiments R^(4d) is halogen.

In some embodiments R^(4d) is CN.

In some embodiments R^(4d) is C₁₋₆ linear alkyl.

In some embodiments R^(4d) is C₃₋₇ branched alkyl,

In some embodiments R^(4d) is C₃₋₇ cycloalkyl.

In some embodiments R^(4d) is C₁₋₆ linear alkoxy.

In some embodiments R^(4d) is C₃₋₇ branched alkoxy.

In some embodiments R^(4d) is C₃₋₇ cycloalkoxy.

In some embodiments R^(4d) is C₁₋₆ linear haloalkyl.

In some embodiments R^(4d) is C₃₋₇ branched haloalkyl.

In some embodiments R^(4d) is C₁₋₆ linear haloalkoxy,

In some embodiments R^(4d) is —S(C₁₋₆ linear alkyl),

In some embodiments R^(4d) is —S(C₃₋₇ branched alkyl),

In some embodiments R^(4d) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(4d) is —SO₂(C₁₋₆ linear alkyl),

In some embodiments R^(4d) is —SO₂(C₃₋₇ branched alkyl),

In some embodiments R^(4d) is —SO₂(C₃₋₇ cycloalkyl).

In some embodiments R^(4d) is COR⁵.

In some embodiments R^(4d) is CO₂R⁶.

In some embodiments R^(4d) is CONR^(7a)R^(7b).

In some embodiments R^(4d) is SO₂NR^(7a)R^(7b),

In some embodiments R^(4d) is NR^(8a)R^(8b).

In some embodiments R^(4d) is NR^(8a)COR⁹.

In some embodiments R^(4d) is NR^(8a)SO₂R¹⁰.

In some embodiments R^(4d) is NR^(8a)SO₂NR^(11a)R^(11b).

In some embodiments R⁵ is hydrogen.

In some embodiments R⁵ is C₁₋₆ linear alkyl.

In some embodiments R⁵ is C₃₋₇ branched alkyl.

In some embodiments R³ is C₃₋₇ cycloalkyl.

In some embodiments R⁶ is C₁₋₆ linear alkyl.

In some embodiments R⁶ is C₃₋₇ branched alkyl.

In some embodiments R⁶ is C₃₋₇ cycloalkyl.

In some embodiments R^(7a) is hydrogen.

In some embodiments R^(7a) is C₁₋₆ linear alkyl.

In some embodiments R^(7a) is C₃₋₇ branched alkyl.

In some embodiments R^(7a) is C₃₋₇ cycloalkyl.

In some embodiments R^(7b) is hydrogen.

In some embodiments R^(7b) is C₁₋₆ linear alkyl.

In some embodiments R^(7b) is C₃₋₇ branched alkyl.

In some embodiments R^(7b) is C₃₋₇ cycloalkyl.

In some embodiments R^(8a) is hydrogen.

In some embodiments R^(8a) is C₁₋₆ linear alkyl.

In some embodiments R^(8a) is C₃₋₇ branched alkyl.

In some embodiments R^(8a) is C₃₋₇ cycloalkyl.

In some embodiments R^(8b) is hydrogen.

In some embodiments R^(8b) is C₁₋₆ linear alkyl.

In some embodiments R^(8b) is C₃₋₇ branched alkyl.

In some embodiments R^(8b) is C₃₋₇ cycloalkyl.

In some embodiments R^(8a) and R^(8b) are taken together with the atomto which they are bound to form a ring having 3 ring atoms.

In some embodiments R^(8a) and R^(8b) are taken together with the atomto which they are bound to form a ring having 4 ring atoms.

In some embodiments R^(8a) and R^(8b) are taken together with the atomto which they are bound to form a ring having 5 ring atoms.

In some embodiments R^(8a) and R^(8b) are taken together with the atomto which they are bound to form a ring having 6 ring atoms optionallycontaining an oxygen.

In some embodiments R^(8a) and R^(8b) are taken together with the atomto which they are bound to form a ring having 7 ring atoms optionallycontaining an oxygen.

In some embodiments R⁹ is hydrogen.

In some embodiments R⁹ is C₁₋₆ linear alkyl.

In some embodiments R⁹ is C₃₋₇ branched alkyl.

In some embodiments R⁹ is C₃₋₇ cycloalkyl.

In some embodiments R¹⁰ is C₁₋₆ linear alkyl.

In some embodiments R¹⁰ is C₃₋₇ branched alkyl.

In some embodiments R¹⁰ is C₃₋₇ cycloalkyl.

In some embodiments R^(11a) is hydrogen

In some embodiments R^(11a) is C₁₋₆ linear alkyl.

In some embodiments R^(11a) is C₃₋₇ branched alkyl.

In some embodiments R^(11a) is C₃₋₇ cycloalkyl.

In some embodiments R^(11b) is hydrogen

In some embodiments R^(11b) is C₁₋₆ linear alkyl.

In some embodiments R^(11b) is C₃, branched alkyl.

In some embodiments R^(11b) is C₃₋₇ cycloalkyl.

Examples of compounds of the invention include, but are not limited to:

-   (R)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (S)-3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one;-   (R)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (S)-2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (R)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (S)-3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (R)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (S)-4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile;-   (R)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(2-hydroxy    phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (R)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   (S)-3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one;-   or a pharmaceutically acceptable form thereof.

Exemplary embodiments include compounds having the formula (T) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(1a), R^(1b), R² and n are definedherein below in Table 1.

TABLE 1 Entry n R^(1a) R^(1b) R² 1 1 CH₃ CH₃ Phenyl 2 2 CH₃ CH₃ Phenyl 33 CH₃ CH₃ Phenyl 4 1 CH₂CH₃ CH₂CH₃ Phenyl 5 2 CH₂CH₃ CH₂CH₃ Phenyl 6 3CH₂CH₃ CH₂CH₃ Phenyl 7 1 CH₃ CH₃ 4-OH-phenyl 8 2 CH₃ CH₃ 4-OH-phenyl 103 CH₃ CH₃ 4-OH-phenyl 11 1 CH₂CH₃ CH₂CH₃ 4-OH-phenyl 12 2 CH₂CH₃ CH₂CH₃4-OH-phenyl 13 3 CH₂CH₃ CH₂CH₃ 4-OH-phenyl 14 1 CH₃ CH₃ 3-OH-phenyl 15 2CH₃ CH₃ 3-OH-phenyl 16 3 CH₃ CH₃ 3-OH-phenyl 17 1 CH₂CH₃ CH₂CH₃3-OH-phenyl 18 2 CH₂CH₃ CH₂CH₃ 3-OH-phenyl 19 3 CH₂CH₃ CH₂CH₃3-OH-phenyl 20 1 CH₃ CH₃ 2-OH-phenyl 21 2 CH₃ CH₃ 2-OH-phenyl 22 3 CH₃CH₃ 2-OH-phenyl 23 1 CH₂CH₃ CH₂CH₃ 2-OH-phenyl 24 2 CH₂CH₃ CH₂CH₃2-OH-phenyl 25 3 CH₂CH₃ CH₂CH₃ 2-OH-phenyl 26 1 CH₃ CH₃ 4-CH₃-Phenyl 272 CH₃ CH₃ 4-CH₃-Phenyl 28 3 CH₃ CH₃ 4-CH₃-Phenyl 26 1 CH₂CH₃ CH₂CH₃4-CH₃-Phenyl 30 2 CH₂CH₃ CH₂CH₃ 4-CH₃-Phenyl 31 3 CH₂CH₃ CH₂CH₃4-CH₃-Phenyl 32 1 CH₃ CH₃ 3-CH₃-Phenyl 33 2 CH₃ CH₃ 3-CH₃-Phenyl 34 3CH₃ CH₃ 3-CH₃-Phenyl 35 1 CH₂CH₃ CH₂CH₃ 3-CH₃-Phenyl 36 2 CH₂CH₃ CH₂CH₃3-CH₃-Phenyl 37 3 CH₂CH₃ CH₂CH₃ 3-CH₃-Phenyl 38 1 CH₃ CH₃ 2-CH₃-Phenyl39 2 CH₃ CH₃ 2-CH₃-Phenyl 40 3 CH₃ CH₃ 2-CH₃-Phenyl 41 1 CH₂CH₃ CH₂CH₃2-CH₃-Phenyl 42 2 CH₂CH₃ CH₂CH₃ 2-CH₃-Phenyl 43 3 CH₂CH₃ CH₂CH₃2-CH₃-Phenyl 44 1 CH₃ CH₃ 4-OCH₃-Phenyl 45 2 CH₃ CH₃ 4-OCH₃-Phenyl 46 3CH₃ CH₃ 4-OCH₃-Phenyl 47 1 CH₂CH₃ CH₂CH₃ 4-OCH₃-Phenyl 48 2 CH₂CH₃CH₂CH₃ 4-OCH₃-Phenyl 49 3 CH₂CH₃ CH₂CH₃ 4-OCH₃-Phenyl 50 1 CH₃ CH₃3-OCH₃-Phenyl 51 2 CH₃ CH₃ 3-OCH₃-Phenyl 52 3 CH₃ CH₃ 3-OCH₃-Phenyl 53 1CH₂CH₃ CH₂CH₃ 3-OCH₃-Phenyl 54 2 CH₂CH₃ CH₂CH₃ 3-OCH₃-Phenyl 55 3 CH₂CH₃CH₂CH₃ 3-OCH₃-Phenyl 56 1 CH₃ CH₃ 2-OCH₃-Phenyl 57 2 CH₃ CH₃2-OCH₃-Phenyl 58 3 CH₃ CH₃ 2-OCH₃-Phenyl 59 1 CH₂CH₃ CH₂CH₃2-OCH₃-Phenyl 60 2 CH₂CH₃ CH₂CH₃ 2-OCH₃-Phenyl 61 3 CH₂CH₃ CH₂CH₃2-OCH₃-Phenyl 62 1 CH₃ CH₃ 4-CN-Phenyl 63 2 CH₃ CH₃ 4-CN-Phenyl 64 3 CH₃CH₃ 4-CN-Phenyl 65 1 CH₂CH₃ CH₂CH₃ 4-CN-Phenyl 66 2 CH₂CH₃ CH₂CH₃4-CN-Phenyl 67 3 CH₂CH₃ CH₂CH₃ 4-CN-Phenyl 68 1 CH₃ CH₃ 3-CN-Phenyl 69 2CH₃ CH₃ 3-CN-Phenyl 70 3 CH₃ CH₃ 3-CN-Phenyl 71 1 CH₂CH₃ CH₂CH₃3-CN-Phenyl 72 2 CH₂CH₃ CH₂CH₃ 3-CN-Phenyl 73 3 CH₂CH₃ CH₂CH₃3-CN-Phenyl 74 1 CH₃ CH₃ 2-CN-Phenyl 75 2 CH₃ CH₃ 2-CN-Phenyl 76 3 CH₃CH₃ 2-CN-Phenyl 77 1 CH₂CH₃ CH₂CH₃ 2-CN-Phenyl 78 2 CH₂CH₃ CH₂CH₃2-CN-Phenyl 79 3 CH₂CH₃ CH₂CH₃ 2-CN-Phenyl 80 1 CH₃ CH₃ 4-F-Phenyl 81 2CH₃ CH₃ 4-F-Phenyl 82 3 CH₃ CH₃ 4-F-Phenyl 83 1 CH₂CH₃ CH₂CH₃ 4-F-Phenyl84 2 CH₂CH₃ CH₂CH₃ 4-F-Phenyl 85 3 CH₂CH₃ CH₂CH₃ 4-F-Phenyl 86 1 CH₃ CH₃3-F-Phenyl 87 2 CH₃ CH₃ 3-F-Phenyl 88 3 CH₃ CH₃ 3-F-Phenyl 89 1 CH₂CH₃CH₂CH₃ 3-F-Phenyl 90 2 CH₂CH₃ CH₂CH₃ 3-F-Phenyl 91 3 CH₂CH₃ CH₂CH₃3-F-Phenyl 92 1 CH₃ CH₃ 2-F-Phenyl 93 2 CH₃ CH₃ 2-F-Phenyl 94 3 CH₃ CH₃2-F-Phenyl 95 1 CH₂CH₃ CH₂CH₃ 2-F-Phenyl 96 2 CH₂CH₃ CH₂CH₃ 2-F-Phenyl97 3 CH₂CH₃ CH₂CH₃ 2-F-Phenyl 98 1 CH₃ CH₃ 4-Cl-Phenyl 99 2 CH₃ CH₃4-Cl-Phenyl 100 3 CH₃ CH₃ 4-Cl-Phenyl 101 1 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl102 2 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl 103 3 CH₂CH₃ CH₂CH₃ 4-Cl-Phenyl 104 1CH₃ CH₃ 3-Cl-Phenyl 105 2 CH₃ CH₃ 3-Cl-Phenyl 106 3 CH₃ CH₃ 3-Cl-Phenyl107 1 CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 108 2 CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 109 3CH₂CH₃ CH₂CH₃ 3-Cl-Phenyl 110 1 CH₃ CH₃ 2-Cl-Phenyl 111 2 CH₃ CH₃2-Cl-Phenyl 112 3 CH₃ CH₃ 2-Cl-Phenyl 113 1 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl114 2 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl 115 3 CH₂CH₃ CH₂CH₃ 2-Cl-Phenyl 116 1CH₃ CH₃ 4-Br-Phenyl 117 2 CH₃ CH₃ 4-Br-Phenyl 118 3 CH₃ CH₃ 4-Br-Phenyl119 1 CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 120 2 CH₂CH₃ CH₂CH₃ 4-Br-Phenvl 121 3CH₂CH₃ CH₂CH₃ 4-Br-Phenyl 122 1 CH₃ CH₃ 4-OCF₃-Phenyl 123 2 CH₃ CH₃4-OCF₃-Phenyl 124 3 CH₃ CH₃ 4-OCF₃-Phenyl 125 1 CH₂CH₃ CH₂CH₃4-OCF₃-Phenyl 126 2 CH₂CH₃ CH₂CH₃ 4-OCF₃-Phenyl 127 3 CH₂CH₃ CH₂CH₃4-OCF₃-Phenyl 128 1 CH₃ CH₃ 3-OCF₃-Phenyl 129 2 CH₃ CH₃ 3-OCF₃-Phenyl130 3 CH₃ CH₃ 3-OCF₃-Phenyl 131 1 CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 132 2CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 133 3 CH₂CH₃ CH₂CH₃ 3-OCF₃-Phenyl 134 1 CH₃CH₃ 2-OCF₃-Phenyl 135 2 CH₃ CH₃ 2-OCF₃-Phenyl 136 3 CH₃ CH₃2-OCF₃-Phenyl 137 1 CH₂CH₃ CH₂CH₃ 2-OCF₃-Phenyl 138 2 CH₂CH₃ CH₂CH₃2-OCF₃-Phenyl 139 3 CH₂CH₃ CH₂CH₃ 2-OCF₃-Phenyl 140 1 CH₃ CH₃4-isopropyl-phenyl 141 2 CH₃ CH₃ 4-isopropyl-phenyl 142 3 CH₃ CH₃4-isopropyl-phenyl 143 1 CH₂CH₃ CH₂CH₃ 4-isopropyl-phenyl 144 2 CH₂CH₃CH₂CH₃ 4-isopropyl-phenyl 145 3 CH₂CH₃ CH₂CH₃ 4-isopropyl-phenyl 146 1CH₃ CH₃ 3-isopropyl-phenyl 147 2 CH₃ CH₃ 3-isopropyl-phenyl 148 3 CH₃CH₃ 3-isopropyl-phenyl 149 1 CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl 150 2CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl 151 3 CH₂CH₃ CH₂CH₃ 3-isopropyl-phenyl152 1 CH₃ CH₃ 2-isopropyl-phenyl 153 2 CH₃ CH₃ 2-isopropyl-phenyl 154 3CH₃ CH₃ 2-isopropyl-phenyl 155 1 CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl 156 2CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl 157 3 CH₂CH₃ CH₂CH₃ 2-isopropyl-phenyl158 1 CH₃ CH₃ 4-cyclopropyl-phenyl 159 2 CH₃ CH₃ 4-cyclopropyl-phenyl160 3 CH₃ CH₃ 4-cyclopropyl-phenyl 161 1 CH₂CH₃ CH₂CH₃4-cyclopropyl-phenyl 162 2 CH₂CH₃ CH₂CH₃ 4-cyclopropyl-phenyl 163 3CH₂CH₃ CH₂CH₃ 4-cyclopropyl-phenyl 164 1 CH₃ CH₃ 3-cyclopropyl-phenyl165 2 CH₃ CH₃ 3-cyclopropyl-phenyl 166 3 CH₃ CH₃ 3-cyclopropyl-phenyl167 1 CH₂CH₃ CH₂CH₃ 3-cyclopropyl-phenyl 168 2 CH₂CH₃ CH₂CH₃3-cyclopropyl-phenyl 169 3 CH₂CH₃ CH₂CH₃ 3-cyclopropyl-phenyl 170 1 CH₃CH₃ 2-cyclopropyl-phenyl 171 2 CH₃ CH₃ 2-cyclopropyl-phenyl 172 3 CH₃CH₃ 2-cyclopropyl-phenyl 173 1 CH₂CH₃ CH₂CH₃ 2-cyclopropyl-phenyl 174 2CH₂CH₃ CH₂CH₃ 2-cyclopropyl-phenyl 175 3 CH₂CH₃ CH₂CH₃2-cyclopropyl-phenyl 176 1 CH₃ CH₃ 4-morpholino-phenyl 177 2 CH₃ CH₃4-morpholino-phenyl 178 3 CH₃ CH₃ 4-morpholino-phenyl 179 1 CH₂CH₃CH₂CH₃ 4-morpholino-phenyl 180 2 CH₂CH₃ CH₂CH₃ 4-morpholino-phenyl 181 3CH₂CH₃ CH₂CH₃ 4-morpholino-phenyl 182 1 CH₃ CH₃ 3-morpholino-phenyl 1832 CH₃ CH₃ 3-morpholino-phenyl 184 3 CH₃ CH₃ 3-morpholino-phenyl 185 1CH₂CH₃ CH₂CH₃ 3-morpholino-phenyl 186 2 CH₂CH₃ CH₂CH₃3-morpholino-phenyl 187 3 CH₂CH₃ CH₂CH₃ 3-morpholino-phenyl 188 1 CH₃CH₃ 2-morpholino-phenyl 189 2 CH₃ CH₃ 2-morpholino-phenyl 190 3 CH₃ CH₃2-morpholino-phenyl 191 1 CH₂CH₃ CH₂CH₃ 2-morpholino-phenyl 192 2 CH₂CH₃CH₂CH₃ 2-morpholino-phenyl 193 3 CH₂CH₃ CH₂CH₃ 2-morpholino-phenyl 194 1CH₃ CH₃ 2-pyridyl 195 2 CH₃ CH₃ 2-pyridyl 196 3 CH₃ CH₃ 2-pyridyl 197 1CH₂CH₃ CH₂CH₃ 2-pyridyl 198 2 CH₂CH₃ CH₂CH₃ 2-pyridyl 199 3 CH₂CH₃CH₂CH₃ 2-pyridyl 200 1 CH₃ CH₃ 3-pyridyl 201 2 CH₃ CH₃ 3-pyridyl 202 3CH₃ CH₃ 3-pyridyl 203 1 CH₂CH₃ CH₂CH₃ 3-pyridyl 204 2 CH₂CH₃ CH₂CH₃3-pyridyl 205 3 CH₂CH₃ CH₂CH₃ 3-pyridyl

Exemplary embodiments include compounds having the formula (VI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 2.

TABLE 2 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phenyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 3-OCF₃-Phenyl65 2 3-OCF₃-Phenyl 66 3 3-OCF₃-Phenyl 67 1 2-OCF₃-Phenyl 68 22-OCF₃-Phenyl 69 3 2-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl

Exemplary embodiments include compounds having the formula (VII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 3.

TABLE 3 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phenyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 3-OCF₃-Phenyl65 2 3-OCF₃-Phenyl 66 3 3-OCF₃-Phenyl 67 1 2-OCF₃-Phenyl 68 22-OCF₃-Phenyl 69 3 2-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl

Exemplary embodiments include compounds having the formula (VIII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 4.

TABLE 4 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phcnyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 3-OCF₃-Phenyl65 2 3-OCF₃-Phenyl 66 3 3-OCF₃-Phenyl 67 1 2-OCF₃-Phenyl 68 22-OCF₃-Phenyl 69 3 2-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl

Exemplary embodiments include compounds having the formula (IX) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 5.

TABLE 5 Entry n R² 1 1 Phenyl 2 2 Phenyl 3 3 Phenyl 4 1 4-OH-phenyl 5 24-OH-phenyl 6 3 4-OH-phenyl 7 1 3-OH-phenyl 8 2 3-OH-phenyl 9 33-OH-phenyl 10 1 2-OH-phenyl 11 2 2-OH-phenyl 12 3 2-OH-phenyl 13 14-CH₃-Phenyl 14 2 4-CH₃-Phenyl 15 3 4-CH₃-Phenyl 16 1 3-CH₃-Phenyl 17 23-CH₃-Phenyl 18 3 3-CH₃-Phenyl 19 1 2-CH₃-Phenyl 20 2 2-CH₃-Phenyl 21 32-CH₃-Phenyl 22 1 4-OCH₃-Phenyl 23 2 4-OCH₃-Phenyl 24 3 4-OCH₃-Phenyl 251 3-OCH₃-Phenyl 26 2 3-OCH₃-Phenyl 27 3 3-OCH₃-Phenyl 28 1 2-OCH₃-Phenyl29 2 2-OCH₃-Phenyl 30 3 2-OCH₃-Phenyl 31 1 4-CN-Phenyl 32 2 4-CN-Phenyl33 3 4-CN-Phenyl 34 1 3-CN-Phenyl 35 2 3-CN-Phenyl 36 3 3-CN-Phenyl 37 12-CN-Phenyl 38 2 2-CN-Phenyl 39 3 2-CN-Phenyl 40 1 4-F-Phenyl 41 24-F-Phenyl 42 3 4-F-Phenyl 43 1 3-F-Phenyl 44 2 3-F-Phenyl 45 33-F-Phenyl 46 1 2-F-Phenyl 47 2 2-F-Phenyl 48 3 2-F-Phenyl 49 14-Cl-Phenyl 50 2 4-Cl-Phenyl 51 3 4-Cl-Phenyl 52 1 3-Cl-Phenyl 53 23-Cl-Phenyl 54 3 3-Cl-Phenyl 55 1 2-Cl-Phenyl 56 2 2-Cl-Phenyl 57 32-Cl-Phenyl 58 1 4-Br-Phenyl 59 2 4-Br-Phenyl 60 3 4-Br-Phenyl 61 14-OCF₃-Phenyl 62 2 4-OCF₃-Phenyl 63 3 4-OCF₃-Phenyl 64 1 3-OCF₃-Phenyl65 2 3-OCF₃-Phenyl 66 3 3-OCF₃-Phenyl 67 1 2-OCF₃-Phenyl 68 22-OCF₃-Phenyl 69 3 2-OCF₃-Phenyl 70 1 4-isopropyl-phenyl 71 24-isopropyl-phenyl 72 3 4-isopropyl-phenyl 73 1 3-isopropyl-phenyl 74 23-isopropyl-phenyl 75 3 3-isopropyl-phenyl 76 1 2-isopropyl-phenyl 77 22-isopropyl-phenyl 78 3 2-isopropyl-phenyl 79 1 4-cyclopropyl-phenyl 802 4-cyclopropyl-phenyl 81 3 4-cyclopropyl-phenyl 82 13-cyclopropyl-phenyl 83 2 3-cyclopropyl-phenyl 84 3 3-cyclopropyl-phenyl85 1 2-cyclopropyl-phenyl 86 2 2-cyclopropyl-phenyl 87 32-cyclopropyl-phenyl 88 1 4-morpholino-phenyl 89 2 4-morpholino-phenyl90 3 4-morpholino-phenyl 91 1 3-morpholino-phenyl 92 23-morpholino-phenyl 93 3 3-morpholino-phenyl 94 1 2-morpholino-phenyl 952 2-morpholino-phenyl 96 3 2-morpholino-phenyl 97 1 2-pyridyl 98 22-pyridyl 99 3 2-pyridyl 100 1 3-pyridyl 101 2 3-pyridyl 102 3 3-pyridyl

Exemplary embodiments include compounds having the formula (11) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R^(1a), R^(1b), R² and n are definedherein below in Table 6.

TABLE 6 Entry n R^(1a) R^(1b) R² 1 1 CH₃ CH₃ 2-CF₃-Phenyl 2 2 CH₃ CH₃2-CF₃-Phenyl 3 3 CH₃ CH₃ 2-CF₃-Phenyl 4 1 CH₂CH₃ CH₂CH₃ 2-CF₃-Phenyl 5 2CH₂CH₃ CH₂CH₃ 2-CF₃-Phenyl 6 3 CH₂CH₃ CH₂CH₃ 2-CF₃-Phenyl 7 1 CH₃ CH₃3-CF₃-Phenyl 8 2 CH₃ CH₃ 3-CF₃-Phenyl 9 3 CH₃ CH₃ 3-CF₃-Phenyl 10 1CH₂CH₃ CH₂CH₃ 3-CF₃-Phenyl 11 2 CH₂CH₃ CH₂CH₃ 3-CF₃-Phenyl 12 3 CH₂CH₃CH₂CH₃ 3-CF₃-Phenyl 13 1 CH₃ CH₃ 4-CF₃-Phenyl 14 2 CH₃ CH₃ 4-CF₃-Phenyl15 3 CH₃ CH₃ 4-CF₃-Phenyl 16 1 CH₂CH₃ CH₂CH₃ 4-CF₃-Phenyl 17 2 CH₂CH₃CH₂CH₃ 4-CF₃-Phenyl 18 3 CH₂CH₃ CH₂CH₃ 4-CF₃-Phenyl 19 1 CH₃ CH₃2-NH₂-Phenyl 20 2 CH₃ CH₃ 2-NH₂-Phenyl 21 3 CH₃ CH₃ 2-NH₂-Phenyl 22 1CH₂CH₃ CH₂CH₃ 2-NH₂-Phenyl 23 2 CH₂CH₃ CH₂CH₃ 2-NH₂-Phenyl 24 3 CH₂CH₃CH₂CH₃ 2-NH₂-Phenyl 25 1 CH₃ CH₃ 3-NH₂-Phenyl 26 2 CH₃ CH₃ 3-NH₂-Phenyl27 3 CH₃ CH₃ 3-NH₂-Phenyl 28 1 CH₂CH₃ CH₂CH₃ 3-NH₂-Phenyl 29 2 CH₂CH₃CH₂CH₃ 3-NH₂-Phenyl 30 3 CH₂CH₃ CH₂CH₃ 3-NH₂-Phenyl 31 1 CH₃ CH₃4-NH₂-Phenyl 32 2 CH₃ CH₃ 4-NH₂-Phenyl 33 3 CH₃ CH₃ 4-NH₂-Phenyl 34 1CH₂CH₃ CH₂CH₃ 4-NH₂-Phenyl 35 2 CH₂CH₃ CH₂CH₃ 4-NH₂-Phenyl 36 3 CH₂CH₃CH₂CH₃ 4-NH₂-Phenyl 37 1 CH₃ CH₃ 2-tBu-Phenyl 38 2 CH₃ CH₃ 2-tBu-Phenyl39 3 CH₃ CH₃ 2-tBu-Phenyl 40 1 CH₂CH₃ CH₂CH₃ 2-tBu-Phenyl 41 2 CH₂CH₃CH₂CH₃ 2-tBu-Phenyl 42 3 CH₂CH₃ CH₂CH₃ 2-tBu-Phenyl 43 1 CH₃ CH₃3-tBu-Phenyl 44 2 CH₃ CH₃ 3-tBu-Phenyl 45 3 CH₃ CH₃ 3-tBu-Phenyl 46 1CH₂CH₃ CH₂CH₃ 3-tBu-Phenyl 47 2 CH₂CH₃ CH₂CH₃ 3-tBu-Phenyl 48 3 CH₂CH₃CH₂CH₃ 3-tBu-Phenyl 49 1 CH₃ CH₃ 4-tBu-Phenyl 50 2 CH₃ CH₃ 4-tBu-Phenyl51 3 CH₃ CH₃ 4-tBu-Phenyl 52 1 CH₂CH₃ CH₂CH₃ 4-tBu-Phenyl 53 2 CH₂CH₃CH₂CH₃ 4-tBu-Phenyl 54 3 CH₂CH₃ CH₂CH₃ 4-tBu-Phenyl 55 1 CH₃ CH₃2-NO₂-Phenyl 56 2 CH₃ CH₃ 2-NO₂-Phenyl 57 3 CH₃ CH₃ 2-NO₂-Phenyl 58 1CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 59 2 CH₂CH₃ CH₂CH₃ 2-NO₂-Phenyl 60 3 CH₂CH₃CH₂CH₃ 2-NO₂-Phenyl 61 1 CH₃ CH₃ 3-NO₂-Phenyl 62 2 CH₃ CH₃ 3-NO₂-Phenyl63 3 CH₃ CH₃ 3-NO₂-Phenyl 64 1 CH₂CH₃ CH₂CH₃ 3-NO₂-Phenyl 65 2 CH₂CH₃CH₂CH₃ 3-NO₂-Phenyl 66 3 CH₂CH₃ CH₂CH₃ 3-NO₂-Phenyl 67 1 CH₃ CH₃4-NO₂-Phenyl 68 2 CH₃ CH₃ 4-NO₂-Phenyl 69 3 CH₃ CH₃ 4-NO₂-Phenyl 70 1CH₂CH₃ CH₂CH₃ 4-NO₂-Phenyl 71 2 CH₂CH₃ CH₂CH₃ 4-NO₂-Phenyl 72 3 CH₂CH₃CH₂CH₃ 4-NO₂-Phenyl 73 1 CH₃ CH₃ 2-SCH₃-Phenyl 74 2 CH₃ CH₃2-SCH₃-Phenyl 75 3 CH₃ CH₃ 2-SCH₃-Phenyl 76 1 CH₂CH₃ CH₂CH₃2-SCH₃-Phenyl 77 2 CH₂CH₃ CH₂CH₃ 2-SCH₃-Phenyl 78 3 CH₂CH₃ CH₂CH₃2-SCH₃-Phenyl 79 1 CH₃ CH₃ 3-SCH₃-Phenyl 80 2 CH₃ CH₃ 3-SCH₃-Phenyl 81 3CH₃ CH₃ 3-SCH₃-Phenyl 82 1 CH₂CH₃ CH₂CH₃ 3-SCH₃-Phenyl 83 2 CH₂CH₃CH₂CH₃ 3-SCH₃-Phenyl 84 3 CH₂CH₃ CH₂CH₃ 3-SCH₃-Phenyl 85 1 CH₃ CH₃4-SCH₃-Phenyl 86 2 CH₃ CH₃ 4-SCH₃-Phenyl 87 3 CH₃ CH₃ 4-SCH₃-Phenyl 88 1CH₂CH₃ CH₂CH₃ 4-SCH₃-Phenyl 89 2 CH₂CH₃ CH₂CH₃ 4-SCH₃-Phenyl 90 3 CH₂CH₃CH₂CH₃ 4-SCH₃-Phenyl 91 1 CH₃ CH₃ 2-SO₂CH₃-Phenyl 92 2 CH₃ CH₃2-SO₂CH₃-Phenyl 93 3 CH₃ CH₃ 2-SO₂CH₃-Phenyl 94 1 CH₂CH₃ CH₂CH₃2-SO₂CH₃-Phenyl 95 2 CH₂CH₃ CH₂CH₃ 2-SO₂CH₃-Phenyl 96 3 CH₂CH₃ CH₂CH₃2-SO₂CH₃-Phenyl 97 1 CH₃ CH₃ 3-SO₂CH₃-Phenyl 98 2 CH₃ CH₃3-SO₂CH₃-Phenyl 99 3 CH₃ CH₃ 3-SO₂CH₃-Phenyl 100 1 CH₂CH₃ CH₂CH₃3-SO₂CH₃-Phenyl 101 2 CH₂CH₃ CH₂CH₃ 3-SO₂CH₃-Phenyl 102 3 CH₂CH₃ CH₂CH₃3-SO₂CH₃-Phenyl 103 1 CH₃ CH₃ 4-SO₂CH₃-Phenyl 104 2 CH₃ CH₃4-SO₂CH₃-Phenyl 105 3 CH₃ CH₃ 4-SO₂CH₃-Phenyl 106 1 CH₂CH₃ CH₂CH₃4-SO₂CH₃-Phenyl 107 2 CH₂CH₃ CH₂CH₃ 4-SO₂CH₃-Phenyl 108 3 CH₂CH₃ CH₂CH₃4-SO₂CH₃-Phenyl 109 1 CH₃ CH₃ 2-SO₂NH₂-Phenyl 110 2 CH₃ CH₃2-SO₂NH₂-Phenyl 111 3 CH₃ CH₃ 2-SO₂NH₂-Phenyl 112 1 CH₂CH₃ CH₂CH₃2-SO₂NH₂-Phenyl 113 2 CH₂CH₃ CH₂CH₃ 2-SO₂NH₂-Phenyl 114 3 CH₂CH₃ CH₂CH₃2-SO₂NH₂-Phenyl 115 1 CH₃ CH₃ 3-SO₂NH₂-Phenyl 116 2 CH₃ CH₃3-SO₂NH₂-Phenyl 117 3 CH₃ CH₃ 3-SO₂NH₂-Phenyl 118 1 CH₂CH₃ CH₂CH₃3-SO₂NH₂-Phenyl 119 2 CH₂CH₃ CH₂CH₃ 3-SO₂NH₂-Phenyl 120 3 CH₂CH₃ CH₂CH₃3-SO₂NH₂-Phenyl 121 1 CH₃ CH₃ 4-SO₂NH₂-Phenyl 122 2 CH₃ CH₃4-SO₂NH₂-Phenyl 123 3 CH₃ CH₃ 4-SO₂NH₂-Phenyl 124 1 CH₂CH₃ CH₂CH₃4-SO₂NH₂-Phenyl 125 2 CH₂CH₃ CH₂CH₃ 4-SO₂NH₂-Phenyl 126 3 CH₂CH₃ CH₂CH₃4-SO₂NH₂-Phenyl 127 1 CH₃ CH₃ 2-CONH₂-Phenyl 128 2 CH₃ CH₃2-CONH₂-Phenyl 129 3 CH₃ CH₃ 2-CONH₂-Phenyl 130 1 CH₂CH₃ CH₂CH₃2-CONH₂-Phenyl 131 2 CH₂CH₃ CH₂CH₃ 2-CONH₂-Phenyl 132 3 CH₂CH₃ CH₂CH₃2-CONH₂-Phenyl 133 1 CH₃ CH₃ 3-CONH₂-Phenyl 134 2 CH₃ CH₃ 3-CONH₂-Phenyl135 3 CH₃ CH₃ 3-CONH₂-Phenyl 136 1 CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 137 2CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 138 3 CH₂CH₃ CH₂CH₃ 3-CONH₂-Phenyl 139 1CH₃ CH₃ 4-CONH₂-Phenyl 140 2 CH₃ CH₃ 4-CONH₂-Phenyl 141 3 CH₃ CH₃4-CONH₂-Phenyl 142 1 CH₂CH₃ CH₂CH₃ 4-CONH₂-Phenyl 143 2 CH₂CH₃ CH₂CH₃4-CONH₂-Phenyl 144 3 CH₂CH₃ CH₂CH₃ 4-CONH₂-Phenyl 145 1 CH₃ CH₃2-Br-Phenyl 146 2 CH₃ CH₃ 2-Br-Phenyl 147 3 CH₃ CH₃ 2-Br-Phenyl 148 1CH₂CH₃ CH₂CH₃ 2-Br-Phenyl 149 2 CH₂CH₃ CH₂CH₃ 2-Br-Phenyl 150 3 CH₂CH₃CH₂CH₃ 2-Br-Phenyl 151 1 CH₃ CH₃ 3-Br-Phenyl 152 2 CH₃ CH₃ 3-Br-Phenyl153 3 CH₃ CH₃ 3-Br-Phcnyl 154 1 CH₂CH₃ CH₂CH₃ 3-Br-Phenyl 155 2 CH₂CH₃CH₂CH₃ 3-Br-Phenyl 156 3 CH₂CH₃ CH₂CH₃ 3-Br-Phenyl 157 1 CH₃ CH₃2,3-di-CH₃-phenyl 158 2 CH₃ CH₃ 2,3-di-CH₃-phenyl 159 3 CH₃ CH₃2,3-di-CH₃-phenyl 160 1 CH₂CH₃ CH₂CH₃ 2,3-di-CH₃-phenyl 161 2 CH₂CH₃CH₂CH₃ 2,3-di-CH₃-phenyl 162 3 CH₂CH₃ CH₂CH₃ 2,3-di-CH₃-phenyl 163 1 CH₃CH₃ 2,4-di-CH₃-phenyl 164 2 CH₃ CH₃ 2,4-di-CH₃-phenyl 165 3 CH₃ CH₃2,4-di-CH₃-phenyl 166 1 CH₂CH₃ CH₂CH₃ 2,4-di-CH₃-phenyl 167 2 CH₂CH₃CH₂CH₃ 2,4-di-CH₃-phenyl 168 3 CH₂CH₃ CH₂CH₃ 2,4-di-CH₃-phenyl 169 1 CH₃CH₃ 2,5-di-CH₃-phenyl 170 2 CH₃ CH₃ 2,5-di-CH₃-phenyl 171 3 CH₃ CH₃2,5-di-CH₃-phenyl 172 1 CH₂CH₃ CH₂CH₃ 2,5-di-CH₃-phenyl 173 2 CH₂CH₃CH₂CH₃ 2,5-di-CH₃-phenyl 174 3 CH₂CH₃ CH₂CH₃ 2,5-di-CH₃-phenyl 175 1 CH₃CH₃ 2,6-di-CH₃-phenyl 176 2 CH₃ CH₃ 2,6-di-CH₃-phenyl 177 3 CH₃ CH₃2,6-di-CH₃-phenyl 178 1 CH₂CH₃ CH₂CH₃ 2,6-di-CH₃-phenyl 179 2 CH₂CH₃CH₂CH₃ 2,6-di-CH₃-phenyl 180 3 CH₂CH₃ CH2CH3 2,6-di-CH₃-phenyl 181 1 CH₃CH₃ 3,4-di-CH₃-phenyl 182 2 CH₃ CH₃ 3,4-di-CH₃-phenyl 183 3 CH₃ CH₃3,4-di-CH₃-phenyl 184 1 CH₂CH₃ CH₂CH₃ 3,4-di-CH₃-phenyl 185 2 CH₂CH₃CH₂CH₃ 3,4-di-CH₃-phenyl 186 3 CH₂CH₃ CH₂CH₃ 3,4-di-CH₃-phenyl 187 1 CH₃CH₃ 3,5-di-CH₃-phenyl 188 2 CH₃ CH₃ 3,5-di-CH₃-phenyl 189 3 CH₃ CH₃3,5-di-CH₃-phenyl 190 1 CH₂CH₃ CH₂CH₃ 3,5-di-CH₃-phenyl 191 2 CH₂CH₃CH₂CH₃ 3,5-di-CH₃-phenyl 192 3 CH₂CH₃ CH₂CH₃ 3,5-di-CH₃-phenyl 193 1 CH₃CH₃ 2,3-di-Cl-phenyl 194 2 CH₃ CH₃ 2,3-di-Cl-phenyl 195 3 CH₃ CH₃2,3-di-Cl-phenyl 196 1 CH₂CH₃ CH₂CH₃ 2,3-di-Cl-phenyl 197 2 CH₂CH₃CH₂CH₃ 2,3-di-Cl-phenyl 198 3 CH₂CH₃ CH₂CH₃ 2,3-di-Cl-phenyl 199 1 CH₃CH₃ 2,4-di-Cl-phenyl 200 2 CH₃ CH₃ 2,4-di-Cl-phenyl 201 3 CH₃ CH₃2,4-di-Cl-phenyl 202 1 CH₂CH₃ CH₂CH₃ 2,4-di-Cl-phenyl 203 2 CH₂CH₃CH₂CH₃ 2,4-di-Cl-phenyl 204 3 CH₂CH₃ CH₂CH₃ 2,4-di-Cl-phenyl 205 1 CH₃CH₃ 2,5-di-Cl-phenyl 206 2 CH₃ CH₃ 2,5-di-Cl-phenyl 207 3 CH₃ CH₃2,5-di-Cl-phenyl 280 1 CH₂CH₃ CH₂CH₃ 2,5-di-Cl-phenyl 209 2 CH₂CH₃CH₂CH₃ 2,5-di-Cl-phenyl 210 3 CH₂CH₃ CH₂CH₃ 2,5-di-Cl-phenyl 211 1 CH₃CH₃ 2,6-di-Cl-phenyl 212 2 CH₃ CH₃ 2,6-di-Cl-phenyl 213 3 CH₃ CH₃2,6-di-Cl-phenyl 214 1 CH₂CH₃ CH₂CH₃ 2,6-di-Cl-phenyl 215 2 CH₂CH₃CH₂CH₃ 2,6-di-Cl-phenyl 216 3 CH₂CH₃ CH₂CH₃ 2,6-di-Cl-phenyl 217 1 CH₃CH₃ 3,4-di-Cl-phenyl 218 2 CH₃ CH₃ 3,4-di-Cl-phenyl 219 3 CH₃ CH₃3,4-di-Cl-phenyl 220 1 CH₂CH₃ CH₂CH₃ 3,4-di-Cl-phenyl 221 2 CH₂CH₃CH₂CH₃ 3,4-di-Cl-phenyl 222 3 CH₂CH₃ CH₂CH₃ 3,4-di-Cl-phenyl 223 1 CH₃CH₃ 3,5-di-Cl-phenyl 224 2 CH₃ CH₃ 3,5-di-Cl-phenyl 225 3 CH₃ CH₃3,5-di-Cl-phenyl 226 1 CH₂CH₃ CH₂CH₃ 3,5-di-Cl-phenyl 227 2 CH₂CH₃CH₂CH₃ 3,5-di-Cl-phenyl 228 3 CH₂CH₃ CH₂CH₃ 3,5-di-Cl-phenyl 229 1 CH₃CH₃ 2-morpholino-4-CH₃-phenyl 230 2 CH₃ CH₃ 2-morpholino-4-CH₃-phenyl231 3 CH₃ CH₃ 2-morpholino-4-CH₃-phenyl 232 1 CH₂CH₃ CH₂CH₃2-morpholino-4-CH₃-phenyl 233 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CH₃-phenyl234 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CH₃-phenyl 235 1 CH₃ CH₃2-morpholino-4-CN-phenyl 236 2 CH₃ CH₃ 2-morpholino-4-CN-phenyl 237 3CH₃ CH₃ 2-morpholino-4-CN-phenyl 238 1 CH₂CH₃ CH₂CH₃2-morpholino-4-CN-phenyl 239 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CN-phenyl240 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-CN-phenyl 241 1 CH₃ CH₃2-morpholino-4-OH-phenyl 242 2 CH₃ CH₃ 2-morpholino-4-OH-phenyl 243 3CH₃ CH₃ 2-morpholino-4-OH-phenyl 244 1 CH₂CH₃ CH₂CH₃2-morpholino-4-OH-phenyl 245 2 CH₂CH₃ CH₂CH₃ 2-morpholino-4-OH-phenyl246 3 CH₂CH₃ CH₂CH₃ 2-morpholino-4-OH-phenyl

Exemplary embodiments include compounds having the formula (X) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 7.

TABLE 7 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl

Exemplary embodiments include compounds having the formula (XI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 8.

TABLE 8 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl

Exemplary embodiments include compounds having the formula (XII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 9.

TABLE 9 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl

Exemplary embodiments include compounds having the formula (XIII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R² and n are defined herein below inTable 10.

TABLE 10 Entry n R² 1 1 2-CF₃-Phenyl 2 2 2-CF₃-Phenyl 3 3 2-CF₃-Phenyl 41 3-CF₃-Phenyl 5 2 3-CF₃-Phenyl 6 3 3-CF₃-Phenyl 7 1 4-CF₃-Phenyl 8 24-CF₃-Phenyl 9 3 4-CF₃-Phenyl 10 1 2-NH₂-Phenyl 11 2 2-NH₂-Phenyl 12 32-NH₂-Phenyl 13 1 3-NH₂-Phenyl 14 2 3-NH₂-Phenyl 15 3 3-NH₂-Phenyl 16 14-NH₂-Phenyl 17 2 4-NH₂-Phenyl 18 3 4-NH₂-Phenyl 19 1 2-tBu-Phenyl 20 22-tBu-Phenyl 21 3 2-tBu-Phenyl 22 1 3-tBu-Phenyl 23 2 3-tBu-Phenyl 24 33-tBu-Phenyl 25 1 4-tBu-Phenyl 26 2 4-tBu-Phenyl 27 3 4-tBu-Phenyl 28 12-NO₂-Phenyl 29 2 2-NO₂-Phenyl 30 3 2-NO₂-Phenyl 31 1 3-NO₂-Phenyl 32 23-NO₂-Phenyl 33 3 3-NO₂-Phenyl 34 1 4-NO₂-Phenyl 35 2 4-NO₂-Phenyl 36 34-NO₂-Phenyl 37 1 2-SCH₃-Phenyl 38 2 2-SCH₃-Phenyl 39 3 2-SCH₃-Phenyl 401 3-SCH₃-Phenyl 41 2 3-SCH₃-Phenyl 42 3 3-SCH₃-Phenyl 43 1 4-SCH₃-Phenyl44 2 4-SCH₃-Phenyl 45 3 4-SCH₃-Phenyl 46 1 2-SO₂CH₃-Phenyl 47 22-SO₂CH₃-Phenyl 48 3 2-SO₂CH₃-Phenyl 49 1 3-SO₂CH₃-Phenyl 50 23-SO₂CH₃-Phenyl 51 3 3-SO₂CH₃-Phenyl 52 1 4-SO₂CH₃-Phenyl 53 24-SO₂CH₃-Phenyl 54 3 4-SO₂CH₃-Phenyl 55 1 2-SO₂NH₂-Phenyl 56 22-SO₂NH₂-Phenyl 57 3 2-SO₂NH₂-Phenyl 58 1 3-SO₂NH₂-Phenyl 59 23-SO₂NH₂-Phenyl 60 3 3-SO₂NH₂-Phenyl 61 1 4-SO₂NH₂-Phenyl 62 24-SO₂NH₂-Phenyl 63 3 4-SO₂NH₂-Phenyl 64 1 2-CONH₂-Phenyl 65 22-CONH₂-Phenyl 66 3 2-CONH₂-Phenyl 67 1 3-CONH₂-Phenyl 68 23-CONH₂-Phenyl 69 3 3-CONH₂-Phenyl 70 1 4-CONH₂-Phenyl 71 24-CONH₂-Phenyl 72 3 4-CONH₂-Phenyl 73 1 2-Br-Phenyl 74 2 2-Br-Phenyl 753 2-Br-Phenyl 76 1 3-Br-Phenyl 77 2 3-Br-Phenyl 78 3 3-Br-Phenyl 79 12,3-di-CH₃-phenyl 80 2 2,3-di-CH₃-phenyl 81 3 2,3-di-CH₃-phenyl 82 12,4-di-CH₃-phenyl 83 2 2,4-di-CH₃-phenyl 84 3 2,4-di-CH₃-phenyl 85 12,5-di-CH₃-phenyl 86 2 2,5-di-CH₃-phenyl 87 3 2,5-di-CH₃-phenyl 88 12,6-di-CH₃-phenyl 89 2 2,6-di-CH₃-phenyl 90 3 2,6-di-CH₃-phenyl 91 13,4-di-CH₃-phenyl 92 2 3,4-di-CH₃-phenyl 93 3 3,4-di-CH₃-phenyl 94 13,5-di-CH₃-phenyl 95 2 3,5-di-CH₃-phenyl 96 3 3,5-di-CH₃-phenyl 97 12,3-di-Cl-phenyl 98 2 2,3-di-Cl-phenyl 99 3 2,3-di-Cl-phenyl 100 12,4-di-Cl-phenyl 101 2 2,4-di-Cl-phenyl 102 3 2,4-di-Cl-phenyl 103 12,5-di-Cl-phenyl 104 2 2,5-di-Cl-phenyl 105 3 2,5-di-Cl-phenyl 106 12,6-di-Cl-phenyl 107 2 2,6-di-Cl-phenyl 108 3 2,6-di-Cl-phenyl 109 13,4-di-Cl-phenyl 110 2 3,4-di-Cl-phenyl 111 3 3,4-di-Cl-phenyl 112 13,5-di-Cl-phenyl 113 2 3,5-di-Cl-phenyl 114 3 3,5-di-Cl-phenyl 115 12-morpholino-4-CH₃-phenyl 116 2 2-morpholino-4-CH₃-phenyl 117 32-morpholino-4-CH₃-phenyl 118 1 2-morpholino-4-CN-phenyl 119 22-morpholino-4-CN-phenyl 120 3 2-morpholino-4-CN-phenyl 121 12-morpholino-4-OH-phenyl 122 2 2-morpholino-4-OH-phenyl 123 32-morpholino-4-OH-phenyl

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one.

For the purposes of the present invention, a compound depicted by theracemic formula, for example:

will stand equally well for either of the two enantiomers having theformula:

or the formula:

or mixtures thereof, or in the case where a second chiral center ispresent, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

Process for Preparing the 5-Hydroxytryptamine Receptor 7 ActivityModulators of the Invention

The present invention further relates to a process for preparing the5-hydroxytryptamine receptor 7 activity modulators of the presentinvention.

Compounds of the present teachings can be prepared in accordance withthe procedures outlined herein, from commercially available startingmaterials, compounds known in the literature, or readily preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art. Standard synthetic methods andprocedures for the preparation of organic molecules and functional grouptransformations and manipulations can be readily obtained from therelevant scientific literature or from standard textbooks in the field.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions can vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures. Those skilled in the art of organic synthesiswill recognize that the nature and order of the synthetic stepspresented can be varied for the purpose of optimizing the formation ofthe compounds described herein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of whichis incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

The compounds of these teachings can be prepared by methods known in theart of organic chemistry. The reagents used in the preparation of thecompounds of these teachings can be either commercially obtained or canbe prepared by standard procedures described in the literature. Forexample, compounds of the present invention can be prepared according tothe method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds

The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. In accordance with thisinvention, compounds in the genus may be produced by one of thefollowing reaction schemes.

Compounds of the disclosure may be prepared according to any of theprocess outlined in Schemes 1-5.

Accordingly, a suitably substituted compound (1) a known compound orcompound prepared by known methods, is reacted with a compound of theformula (2), a known compound or a compound prepared by known methods,in the presence of a palladium catalyst such as palladium acetate,palladium bis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), bis(acetonitrile) dichloropalladium[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium,Tris(dibenzylideneacetone)dipalladium(0), and the like, in the presenceof a base such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium carbonate, sodium carbonate, lithium carbonate,cesium carbonate, sodium hydroxide, lithium hydroxide, potassiumhydroxide, and the like, optionally in the presence of an organic basesuch as triethylamine, diisopropylethyl amine, pyridine, and the like,optionally in the presence of a bis(diphenylphosphino) derived compoundsuch as 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene,2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,1,1′-binaphthalene-2,2′-diyl)bis[bis(3,5-dimethylphenyl)phosphine],5,5′-bis[di(3,5-xylyl) phosphino]-4,4′-bi-1,3-benzodioxole,5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole, and the like, in a solvent such astoluene, benzene, xylene, 1,4-dioxane, tetrahydrofuran, methylenechloride, 1,2-dichloroethane, N,N-dimethylformamide,N,N-dimethylacetamide, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (3). Acompound of the formula (3) is reacted with an acid such astrifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like,optionally in the presence of an organic solvent such as methylenechloride, dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol,ethanol, and the like, to provide a compound of the formula (4).

A suitably substituted compound (5), a known compound or compoundprepared by known methods, is reacted with a compound of the formula(6), a known compound or a compound prepared by known methods, in thepresence of a palladium catalyst such as palladium acetate, palladiumbis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), bis(acetonitrile) dichloropalladium[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium,Tris(dibenzylideneacetone)dipalladium(0), and the like, in the presenceof a base such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium carbonate, sodium carbonate, lithium carbonate,cesium carbonate, sodium hydroxide, lithium hydroxide, potassiumhydroxide, and the like, optionally in the presence of an organic basesuch as triethylamine, diisopropylethyl amine, pyridine, and the like,optionally in the presence of a bis(diphenylphosphino) derived compoundsuch as 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene,2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,1,1′-binaphthalene-2,2′-diyl)bis[bis(3,5-dimethylphenyl)phosphine],5,5′-bis[di(3,5-xylyl) phosphino]-4,4′-bi-1,3-benzodioxole,5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole,and the like, in a solvent such as toluene, benzene, xylene,1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (7). A compound of the formula (7) is reactedwith hydrogen in the presence of a palladium catalyst such as palladiumon carbon, palladium on celite, palladium on barium sulfate, palladiumacetate, palladium bis(triphenylphosphine) dichloride, palladiumtetrakis(triphenylphospine), and the like, in a solvent such asmethanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran,1,4-dioxane, and the like to provide a compound of the formula (8).

A suitably substituted compound of formula (9), a known compound orcompound prepared by known methods, is reacted with a compound of theformula (10), wherein X is a leaving group such as chlorine, bromine,iodine, mesylate, tosylate, and the like, in the presence of a base suchas lithium diisopropylamide, sodium diisopropylamide, potassiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodiumhydride, and the like in an organic solvent such as tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide,and the like, to provide a compound of the formula (11). A compound ofthe formula (11) is then treated with paraformaldehyde in the presenceof an acid such as sulfuric acid, hydrochloric acid, and the like, inthe presence of acetic acid, and optionally in an organic solvent suchas methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,dimethylformamide, dimethylacetamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (12). A compound of the formula (12) is then treated with abase such as sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like, in a solvent such as water, methanol, ethanol,isopropanol, and the like, optionally with heating, and then treatedwith an acid such as sulfuric acid, hydrochloric acid, and the like, ina solvent such as water, methanol, ethanol, isopropanol, and the like,to provide a compound of the formula (13). A compound of the formula(13) is then converted to a compound of the formula (14), wherein LG isa leaving group such as mesylate, tosylate, nosylate, bromicde, and thelike, using methods that are known to one skilled in the art. Thus, acompound of the formula (13) is treated with a sulfonyl chloride such asmethanesulfonyl chloride, toluenesulfonyl chloride p-nitrophenylsulfonyl chloride, and the like, in the presence of a base such astriethylamine, diisopropyl amine, pyridine, 2,6-lutidine, and the like,in an organic solvent such as methylene chloride, dichloroethane,tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane and the like to provide a compound of the formula (14).Alternatively, a compound of the formula (13) is reacted with carbontetrabromide in the presence of triphenylphosphine in a solvent such asmethylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like,optionally with heating, optionally with microwave irradiation, toprovide a compound of the formula (14).

A compound of the formula (14) is reacted with a compound of the formula(15), a known compound or compound prepared by known methods, in anorganic solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, 2,6 lutidine, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (16).

A suitably substituted compound of formula (17), a known compound orcompound prepared by known methods, is reacted with a compound of theformula (18), wherein X is a leaving group such as chlorine, bromine,iodine, mesylate, tosylate, and the like, in the presence of a base suchas lithium diisopropylamide, sodium diisopropylamide, potassiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodiumhydride, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, and thelike in an organic solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like,to provide a compound of the formula (19). A compound of the formula(19) is then treated with paraformaldehyde in the presence of an acidsuch as sulfuric acid, hydrochloric acid, and the like, in the presenceof acetic acid, and optionally in an organic solvent such as methanol,ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,dimethylformamide, dimethylacetamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (20). A compound of the formula (20) is then treated with abase such as sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like, in an solvent such as water, methanol, ethanol,isopropanol, and the like, optionally with heating, and then treatedwith an acid such as sulfuric acid, hydrochloric acid, and the like, ina solvent such as water, methanol, ethanol, isopropanol, and the like,optionally with heating, to provide a compound of the formula (21). Acompound of the formula (21) is then converted to a compound of theformula (22), wherein LG is a leaving group such as mesylate, tosylate,nosylate, bromide, and the like, using methods that are known to oneskilled in the art. Thus, a compound of the formula (21) is treated witha sulfonyl chloride such as methanesulfonyl chloride, toluenesulfonylchloride p-nitrophenyl sulfonyl chloride, and the like, in the presenceof a base such as triethylamine, diisopropyl amine, pyridine,2,6-lutidine, and the like, in an organic solvent such as methylenechloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like toprovide a compound of the formula (22). Alternatively, a compound of theformula (21) is reacted with carbon tetrabromide in the presence oftriphenylphosphine in a solvent such as methylene chloride,dichloroethane, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane and the like, optionally with heating,optionally with microwave irradiation, to provide a compound of theformula (22). A compound of the formula (22) is reacted with a compoundof the formula (23), a known compound or compound prepared by knownmethods, in an organic solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like,optionally in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, 2,6 lutidine, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (24).

A compound of the formula (25) is reacted with a base such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,potassium carbonate, lithium carbonate and the like, in the presence ofa solvent such as methanol, ethanol, isopropanol, water, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (26). A compound of the formula (26)is then reacted with iodine in the presence of a base such as sodiumbicarbonate, potassium bicarbonate, lithium bicarbonate, sodiumcarbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide,potassium hydroxide, lithium hydroxide, and the like, in the presence ofa solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane, and thelike to provide a compound of the formula (27). A compound of theformula (27) is reacted with a compound of the formula (28), a knowncompound or compound prepared by known methods, in an organic solventsuch as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,dimethylformamide, dimethylacetamide, and the like, optionally in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6 lutidine, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (29).

A compound of the formula (30) is reacted with ruthenium chloride in thepresence of sodium periodate in a solvent such as acetonitrile,methanol, ethanol, isopropanol, and the like, to provide a compound ofthe formula (31). A compound of the formula (31) is reacted with acompound of the formula (32), a known compound or compound prepared byknown methods, wherein x is a halogen, in the presence of a solvent suchas ethyl ether, tetrahydrofuran, 1,4-dioxane and the like to provide acompound of the formula (33). A compound of the formula (33) is reactedwith ruthenium chloride in the presence of sodium periodate in a solventsuch as acetonitrile, methanol, ethanol, isopropanol, and the like, toprovide a compound of the formula (34). A compound of the formula (34)is reacted with a reducing agent such as lithium borohydride, sodiumborohydride, sodium cyanoborohydride and the like, in a solvent such asmethanol, ethanol, isopropanol, acetonitrile, and the like to provide acompound of the formula (35). A compound of the formula (35) is thenconverted to a compound of the formula (36), wherein LG is a leavinggroup such as mesylate, tosylate, nosylate, bromide, and the like, usingmethods that are known to one skilled in the art. Thus, a compound ofthe formula (35) is treated with a sulfonyl chloride such asmethanesulfonyl chloride, toluenesulfonyl chloride p-nitrophenylsulfonyl chloride, and the like, in the presence of a base such astriethylamine, diisopropyl amine, pyridine, 2,6-lutidine, and the like,in an organic solvent such as methylene chloride, dichloroethane,tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane and the like to provide a compound of the formula (36).Alternatively, a compound of the formula (35) is reacted with carbontetrabromide in the presence of triphenylphosphine in a solvent such asmethylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like,optionally with heating, optionally with microwave irradiation, toprovide a compound of the formula (36). A compound of the formula (36)is reacted with a compound of the formula (37), a known compound orcompound prepared by known methods, in an organic solvent such astetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide,dimethylacetamide, and the like, optionally in the presence of a basesuch as triethylamine, diisopropylethylamine, pyridine, 2,6 lutidine,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (38).

The Examples provided below provide representative methods for preparingexemplary compounds of the present invention. One of ordinary skill inthe art will know how to substitute the appropriate reagents, startingmaterials and purification methods known to those skilled in the art, inorder to prepare the compounds of the present invention.

EXAMPLES

The practice of the invention is illustrated by the followingnon-limiting examples. The Examples provided below providerepresentative methods for preparing exemplary compounds of the presentinvention. One of ordinary skill in the art will know how to substitutethe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, in order to prepare the compounds ofthe present invention.

In the examples that follow, ¹H-NMR spectra were obtained on a VarianMercury 300-MHz NMR. Purity (%) and mass spectral data were determinedwith a Waters Alliance 2695 HPLC/MS (Waters Symmetry CIS, 4.6×75 mm, 3.5m) with a 2996 diode array detector from 210-400 nm.

In the examples that follow, ¹H-NMR spectra were obtained on a VarianMercury 300-MHz NMR. Purity (%) and mass spectral data were determinedwith a Waters Alliance 2695 HPLC/MS (Waters Symmetry CIS, 4.6×75 mm, 3.5μm) with a 2996 diode array detector from 210-400 nm.

Example 1: Preparation of methyl 2,2-dimethylpent-4-enoate: Thisreaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of freshly prepared lithiumdiisopropylamide (1M, 1.10 equiv) in dry 35 ml tetrahydrofuran,isobutyric acid methyl ester (3.32 g, 32.6 mmol, 1.0 equiv) was addeddropwise during 0.5 hours at −78° C. The mixture was allowed to stir atthis temperature for 30 min followed by the addition of allyl bromide(5.35 g, 44.0 mmol) and Hexamethylphosphoramide (HMPA) (2.91 g, 16.3mmol) dropwise over 0.5 h. The reaction mixture was stirred overnight atroom temperature, quenched with 10% HCl (while cooling in ice bath)until acidic (pH=2). The organic layer was separated and the aqueouslayer was extracted with hexanes (3×100 mL). The extract was washed with10% NaHCO₃ (200 mL) and brine (200 mL). The solution was then dried overMgSO₄, concentrated in vacuo and distilled to give pure product. ¹H NMR(400 MHz, CDCl₃) δ 5.73 (dd, J=9.4, 17.7, 1H), 5.04 (dd, J=1.9, 13.5,2H), 4.12 (q, J=7.1, 2H), 2.28 (d, J=7.4, 2H), 1.25 (t, J=7.1, 3H), 1.17(s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 177.42, 134.42, 117.88, 77.68,77.36, 77.04, 60.35, 44.91, 42.25, 24.92, 14.35

The following compounds can be prepared by the procedure of methyl2,2-dimethylpent-4-enoate. One of ordinary skill in the art will knowhow to substitute the appropriate reagents, starting materials andpurification methods known to those skilled in the art, in order toprepare the compounds provided herein.

Example 2: Preparation of Ethyl 2,2-diethylpent-4-enoate: The titlecompound was prepared according to the procedure for methyl2,2-dimethylpent-4-enoate, except 2-ethyl-butyric acid ethyl ester wassubstituted for isobutyric acid methyl ester ¹H NMR (300 MHz, CDCl₃) δ5.68 (dd, J=9.9, 17.2, 1H), 5.16-4.97 (m, 2H), 4.14 (q, J=7.1, 2H), 2.33(d, J=7.4, 2H), 1.59 (dt, J=6.5, 7.5, 5H), 1.26 (t, J=7.1, 3H), 0.80 (t,J=7.5, 6H)

Example 3: Preparation of 1-allylcyclobutanecarboxylic acid: Thisreaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of freshly prepared lithiumdiisopropylamide (1M, 10.76 mmol, 2.30 equiv) in dry 107 mltetrahydrofuran, cyclobutanecarboxylic acid (4.68 g, 46.8 mmol, 1.0equiv) was added dropwise during 0.5 hours at 0° C. The mixture washeated to 50° C. for 6 hours, then cooled to 0° C. followed by theaddition of NaI (0.697 g, 4.68 mmol, 0.1 equiv) in one portion and amixture of allyl bromide (7.58 g, 63.2 mmol, 1.35 equiv) and HMPA (4.18g, 23.4 mmol, 0.5 equiv) dropwise over 0.5 hr. The reaction mixture wasstirred overnight at room temperature, quenched with 10% HCl (whilecooling in ice bath) until acidic (pH=2). The organic layer wasseparated and the aqueous layer was extracted with ether (3×250 mL). Theorganic phases were combined and washed with brine. The solution wasthen dried over MgSO₄ and concentrated in vacuo to afford a crude oilwhich was purified through flash chromatography (silica; ethylacetate/hexanes, 1%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 5.77 (ddt, J=7.1,10.2, 17.2, 1H), 5.17-4.99 (m, 2H), 2.59-2.38 (m, 4H), 2.07-1.84 (m,4H). ¹³C NMR (101 MHz, CDCl₃) δ 184.04, 133.90, 118.19, 47.20, 41.74,29.57, 15.65; Rf, 0.43 (Hexane: Ethyl Acetate 10:1); HRMS (CI): [M+H],calcd for C₈H₁₃O₂, 141.0916; found 141.0911.

The following compounds can be prepared by the procedure of1-allylcyclobutanecarboxylic acid. One of ordinary skill in the art willknow how to substitute the appropriate reagents, starting materials andpurification methods known to those skilled in the art, in order toprepare the compounds provided herein.

Example 4: Preparation of 1-allylcyclopentanecarboxylic acid: The titlecompound was prepared according to the procedure for1-allylcyclobutanecarboxylic acid, except cyclopentane carboxylic acidwas substituted for cyclobutanecarboxylic acid: ¹H NMR (400 MHz, CDCl₃)δ 5.77 (ddt, J=7.2, 10.2, 17.4, 1H), 5.17-4.94 (m, 2H), 2.38 (d, J=7.2,2H), 2.20-2.02 (m, 2H), 1.79-1.47 (m, 6H). ¹³C NMR (101 MHz, CDCl₃) δ184.94, 134.96, 118.02, 53.75, 42.96, 35.89, 25.47. Rf, 0.50 (Hexane:Ethyl Acetate 10:1); HRMS (CI): [M+H], calcd for C₉H₁₅O₂, 155.1072;found 155.1068.

Example 5: Preparation of 1-allylcyclohexanecarboxylic acid: The titlecompound was prepared according to the procedure for1-allylcyclobutanecarboxylic acid, except cyclohexane carboxylic acidwas substituted for cyclobutanecarboxylic acid: ¹H NMR (400 MHz, CDCl₃)δ 12.13 (broad, 1H), 5.83-5.63 (m, 1H), 5.12-5.00 (m, 2H), 2.27 (m, 2H),2.04 (m, 2H), 1.66-1.50 (m, 3H), 1.49-1.33 (m, 2H), 1.33-1.17 (m, 3H).

Example 6: Preparation of5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: A mixture ofglacial acetic acid (28.6 g, 477 mmol, 53.6 equiv), paraformaldehyde(0.80 g, 26.7 mmol, 3.0 equiv) and H₂SO₄ (0.5 g, 4.45 mmol, 0.57 equiv)was stirred for 30 min at 70° C. before methyl 2,2-dimethylpent-4-enoate(1.26 g, 8.9 mmol, 1.0 equiv) was added dropwise during 10 min. Thereaction mixture was then maintained at 70˜80° C. and allowed to stirovernight. Acetic acid was removed under reduced pressure and thereaction was quenched with 10% NaHCO₃ solution. The mixture was thenextracted with ethyl acetate (3×50 mL) and the combined organic phasewas concentrated in vacuo to give a crude oil. The crude oil was usedfor next step without further purification.

A mixture of the crude oil (200 mg, 1.0 mmol, 1 equiv) and 30% NaOH (800mg NaOH, 20 mmol, 20 equiv) aqueous solution was refluxed for 2 hours.The mixture was cooled in an ice bath and excess 30% H₂SO₄ was addeduntil acidic (pH<2). The resulting mixture was extracted with ethylacetate (3×25 mL), the combined organic phase was washed with 10%NaHCO₃, (50 mL), brine (50 mL), dried over MgSO₄ and concentrated invacuo to give a crude product which was further purified by columnchromatography (Ethyl acetate/Hexanes, 10%˜60%)¹H NMR (400 MHz, CDCl₃) δ4.70-4.60 (m, 1H), 3.90-3.78 (m, 2H), 2.22 (dd, J=5.9, 12.7, 1H),1.98-1.87 (m, 2H), 1.80 (dd, J=5.9, 12.7, 1H), 1.28 (d, J=4.8, 6H). 13CNMR (101 MHz, CDCl₃) δ 182.26, 75.01, 59.58, 43.93, 40.62, 38.69, 25.31,24.61; Rf, 0.34 (Hexane: Ethyl Acetate 1:1); Anal. Calcd for C₈H₁₄O₃: C,60.74; H, 8.92. Found: C, 60.47; H, 8.86.

The following compounds can be prepared by the procedure of5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one. One of ordinaryskill in the art will know how to substitute the appropriate reagents,starting materials and purification methods known to those skilled inthe art, in order to prepare the compounds provided herein.

Example 7: Preparation of3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one: The title compoundwas prepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except ethyl2,2-diethylpent-4-enoate was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz, CDCl₃) δ 4.62 (dtd, J=5.3,7.3, 9.5, 1H), 3.78 (t, J=6.1, 2H), 3.20 (s, 1H), 2.19 (dd, J=6.8, 13.1,1H), 1.97-1.81 (m, 3H), 1.70-1.56 (m, 4H), 0.93 (dt, J=7.5, 20.7, 6H);¹³C NMR (101 MHz, CDCl₃) δ 181.46, 75.10, 58.91, 48.77, 39.13, 37.76,29.21, 28.30, 8.83, 8.73; Rf, 0.36 (Hexane: Ethyl Acetate 5:2); Anal.Calcd for C₁₀H₁₈O₃: C, 64.49; H, 9.74. Found: C, 64.20; H, 9.57.

Example 8: Preparation of 7-(2-hydroxyethyl)-6-oxaspiro[3.4]octan-5-one:The title compound was prepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except1-allylcyclobutanecarboxylic acid was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz, CDCl₃) δ 4.60-4.50 (m, 1H),3.82 (t, J=5.9, 2H), 2.61-2.40 (m, 3H), 2.19-1.96 (m, 5H). 1.92-185 (m,2H); ¹³C NMR (101 MHz, CDCl₃) δ 181.25, 75.46, 59.66, 44.62, 42.42,38.47, 31.95, 29.64, 16.79; Rf, 0.40 (Hexane: Ethyl Acetate 1:2); calcdfor C₉H₁₅O₃, 171.1021; found 171.1016.

Example 9: Preparation of 3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one:The title compound was prepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except1-allylcyclopentanecarboxylic acid was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz, CDCl₃) δ 4.65-4.56 (m, 1H),3.84-3.76 (m, 2H), 2.74 (s, 1H), 2.28 (dd, J=5.8, 12.6, 1H), 2.20-2.10(m, 1H), 2.00-1.56 (m, 10H); ¹³C NMR (101 MHz, CDCl₃) δ 183.02, 75.77,59.20, 50.35, 43.41, 38.41, 37.49, 36.93. 25.67, 25.58; Rf. 0.46(Hexane: Ethyl Acetate 1:2); HRMS (CI): [M+H], calcd for C₁₀H₁₇O₃,185.1178; found 185.1171.

Example 10: Preparation of3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one: The title compound wasprepared according to the procedure for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one, except1-allylcyclohexanecarboxylic acid was substituted for methyl2,2-dimethylpent-4-enoate: ¹H NMR (400 MHz. CDCl₃) δ 4.62 (m, 1H), 3.82(t, J=5.9, 2H), 2.43 (dd, J=6.2, 12.9, 1H), 2.22 (s, 1H), 2.00-1.17 (m,13H). ¹³C NMR (101 MHz, CDCl₃) δ 181.96, 75.37, 59.55, 45.13, 39.88,38.91, 34.54, 31.71, 25.57, 22.42, 22.36; Rf, 0.46 (Hexane: EthylAcetate 1:2); Anal. Calcd for C₁₁H₁₈O₃: C, 66.64; H, 9.15. Found: C,66.48; H, 9.17.

Example 11: Preparation of2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate: To a stirred solution of5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one (0.316 g, 2 mmol,1.0 equiv) and Et₃N (0.152 g, 1.5 mmol, 1.5 equiv) in drydichloromethane, a solution of p-TosCl (0.475 g, 2.5 mmol, 1.25 equiv)in dichloromethane was added drop wise at 0° C. The resulting mixturewas stirred at 0° C. for 1 hour and allowed to stir overnight at roomtemperature. Then, the reaction mixture was diluted with dichloromethane(50 mL), washed with 10% HCl, brine, dried over MgSO₄ and concentratedin vacuo to afford yellowish oil. This crude product was then purifiedby flash chromatography (silica gel; Ethyl acetate/Hexanes, 0%˜40%) toafford desired tosylate. ¹H NMR (300 MHz, CDCl₃) δ 7.72 (m, 2H), 7.29(m, 2H), 4.39 (m, 1H), 4.10 (m, 2H), 2.38 (s, 3H), 2.09 (m. 1H), 1.93(m, 2H), 1.65 (m, 1H), 1.16 (d, J=4.8, 6H); ¹³C NMR (101 MHz, CDCl₃) ¹³CNMR (101 MHz, CDCl₃) δ 181.26, 145.16, 132.53, 130.03, 127.84, 77.68,77.36, 77.04, 72.93, 66.83, 42.99, 40.23, 34.97, 24.82. 24.12, 21.57;HRMS (CI): [M+H] 313.1; Anal. Calcd for C₁₅H₂₀O₅S: C, 57.67; H, 6.45.Found: C, 57.85; H, 6.63.

The following compounds can be prepared by the procedure of2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate. One of ordinary skill in the art will know howto substitute the appropriate reagents, starting materials andpurification methods known to those skilled in the art, in order toprepare the compounds provided herein.

Example 12: Preparation of2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl 4-methylbenzenesulfonate:The title compound was prepared according to the procedure for2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (300 MHz,CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.55-4.33 (m,1H), 4.14 (dd, J=6.5, 13.3 Hz, 3H), 2.46 (s, 3H). 2.21-1.84 (m, 3H),1.83-1.68 (m, 1H), 1.58 (t, J=7.4 Hz, 4H), 0.89 (dt, J=7.5, 18.0 Hz,6H); ¹³C NMR (101 MHz, CDCl₃) δ 180.33, 145.30, 132.72, 130.15, 128.03,77.68, 77.36, 77.04, 73.18, 66.95, 48.67, 37.53, 35.82, 29.14, 28.23,21.76, 8.81, 8.74. Anal. Calcd for C₁₇H₂₄O₅S: C, 59.98; H, 7.11. Found:C, 60.27; H, 7.25.

Example 13: Preparation of 2-(5-oxo-6-oxaspiro[3.4]octan-7-yl)ethyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except7-(2-hydroxyethyl)-6-oxaspiro[3.4]octan-5-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (400 MHz,CDCl₃) δ 7.77 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.37 (tdd,J=8.8, 6.0, 4.3 Hz, 1H), 4.21-4.05 (m, 2H), 2.57-2.32 (m, 6H), 2.19-1.82(in, 7H); ¹³C NMR (101 MHz, CDCl₃) δ 180.41, 145.24, 132.68, 130.10,128.02, 73.38, 66.76, 44.33, 41.79, 35.10, 31.72, 29.28, 21.76, 16.51.

Example 14: Preparation of 2-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)ethyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except3-(2-hydroxyethyl)-2-oxaspiro[4.4]nonan-1-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (400 MHz,CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.51-4.35 (m,1H), 4.25-4.06 (m, 2H), 2.45 (s, 3H), 2.28-2.08 (m, 2H), 2.08-1.91 (m,2H), 1.87-1.52 (m, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 181.90, 145.26,132.76, 130.12, 128.07, 73.71, 66.85, 50.19, 43.07, 37.44, 36.81, 35.19,25.61, 25.50, 21.79.

Example 15: Preparation of 2-(1-oxo-2-oxaspiro[4.5]decan-3-yl)ethyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 2-(4,4-dimethyl-5-oxotetrahydrofuran-2-yl)ethyl4-methylbenzenesulfonate, except3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one was substituted for5-(2-Hydroxy-ethyl)-3,3-dimethyl-dihydro-furan-2-one: ¹H NMR (400 MHz,CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.51-4.38 (m,1H), 4.26-4.12 (m, 2H), 2.45 (s. 3H), 2.36 (dd, J=12.9, 6.2 Hz, 1H).2.12-1.87 (m, 2H), 1.85-1.68 (m, 3H), 1.65-1.50 (m, 5H), 1.43-1.14 (m,3H); 13C NMR (101 MHz, CDCl₃) δ 180.97, 145.27, 132.76, 130.12, 128.07,73.28, 66.85, 44.96, 39.48, 35.58, 34.35, 31.52, 25.37, 22.23, 22.16,21.80.

Example 16: Preparation of 2,2-diethylpent-4-enoic acid: Ethyl2,2-diethylpent-4-enoate (0.2 g, 0.28 mmol) is mixed with NaOH (0.4 g,10 mmol), MeOH (2.5 mL) and H₂O (2.5 mL) in a microwave vial. Themixture is then heated in a microwave reactor at 160° C. for 2 hours.The mixture was then acidified with 10% HCl, washed with ether (3×30ml). The combined organic phase was dried over MgSO₄ and concentrated invacuo to give a crude product which was used in the next step withoutfurther purification.

Example 17: Preparation of3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one:2,2-diethylpent-4-enoic acid (1.77 g, 11.67 mmol) is stirred withtetrahydrofuran (34 mL), ether (12 mL) and saturated NaHCO₃ solution (57mL). The mixture is protected from sunlight. I₂ was dissolved in 12 mLof tetrahydrofuran and added to the mixture in one portion at 0° C. Themixture was allowed to stir overnight at room temperature. Saturatedsodium thiosulfate is added to the mixture to quench the reaction. Themixture was extracted with ethyl acetate (3×50 mL). The combined organicphase was dried over MgSO₄ and concentrated in vacuo to give a crude oilwhich was purified by flash chromatography (silica gel; Ethylacetate/Hexanes, 0%˜25%). ¹H NMR (400 MHz, CDCl₃) δ 4.42 (dtd, J=9.0,7.3, 4.6 Hz, 1H), 3.41 (dd, J=10.2, 4.6 Hz, 1H), 3.23 (dd, J=10.2, 7.5Hz, 1H), 2.25 (dd, J=13.3, 6.9 Hz, 1H), 1.86 (dd, J=13.3, 9.1 Hz, 1H),1.63 (m, 4H), 0.94 (dt, J=10.4, 7.5 Hz, 6H). MS (LC/MS, M+H⁺): 283.0

The following compounds can be prepared by the procedure of3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one. One of ordinary skillin the art will know how to substitute the appropriate reagents,starting materials and purification methods known to those skilled inthe art, in order to prepare the compounds provided herein.

Example 18: Preparation of 3-(iodomethyl)-2-oxaspiro[4.4]nonan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one, except1-allylcyclopentanecarboxylic acid was substituted for2,2-diethylpent-4-enoic acid: ¹H NMR (400 MHz, CDCl₃) δ 4.48-4.34 (m,1H), 3.39 (dd, J=10.2, 4.9 Hz. 1H), 3.23 (dd, J=10.2, 7.5 Hz, 1H), 2.35(dd, J=12.9, 6.1 Hz, 1H), 2.20-2.04 (m, 1H), 1.93-1.54 (m, 8H); ¹³C NMR(101 MHz, CDCl₃) δ 181.57, 75.96, 50.71, 43.44, 37.84, 36.89, 25.45,25.36, 7.02; MS (LC/MS, M+H⁺): 281.0

Example 19: Preparation of 3-(iodomethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(iodomethyl)dihydrofuran-2(3H)-one, except1-allylcyclohexanecarboxylic acid was substituted for2,2-diethylpent-4-enoic acid: ¹H NMR (400 MHz, CDCl₃) δ 4.42 (dtd,J=9.2, 6.9, 4.6 Hz, 1H), 3.41 (dd, J=10.3, 4.6 Hz, 1H), 3.26 (dd,J=10.2, 7.3 Hz, 1H), 2.50 (dd, J=13.1, 6.5 Hz, 1H), 1.85-1.49 (m, 8H),1.44-1.20 (m, 3H); MS (LC/MS, M+H⁺): 295.0

Example 20: Preparation of 3-hydroxy-2-oxaspiro[4.4]nonan-1-one: To astirred mixture of 1-allylcyclopentanecarboxylic acid (10.93 g, 71 mmol,1 equiv), RuCl₃ stock solution (0.514 g, 0.035M in water, 0.035 equiv)and CH₃CN (500 mL), NaIO₄ (30.8 g, 142 mmol, 2.04 equiv) was added inportions over a period of 30 min at room temperature. The suspension wasallowed to stir at room temperature for another 30 min. The reaction wasquenched with saturated aqueous solution of Na₂S₂O₃ and the two layerswere separated. The aqueous layer was extracted with ethyl acetate(3×200 mL). The combined organic layer was washed with brine, dried overanhydrous MgSO₄, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel; Ethyl acetate/Hexanes, 10%˜50%)to give desired product. ¹H NMR (400 MHz, CDCl₃) δ 5.87 (s, 1H), 5.28(s, 1H), 2.06 (dd, J=35.1, 28.9 Hz, 4H), 1.90-1.44 (m, 6H); ¹³C NMR (101MHz, CDCl₃) δ 183.20, 49.58, 43.94, 38.28, 25.42.

The following compounds can be prepared by the procedure of3-hydroxy-2-oxaspiro[4.4]nonan-1-one. One of ordinary skill in the artwill know how to substitute the appropriate reagents, starting materialsand purification methods known to those skilled in the art, in order toprepare the compounds provided herein.

Example 21: Preparation of 3-hydroxy-2-oxaspiro[4.5]decan-1-one: Thetitle compound was prepared according to the procedure for3-hydroxy-2-oxaspiro[4.4]nonan-1-one, except1-allylcyclohexanecarboxylic acid was substituted for1-allylcyclopentanecarboxylic acid: ¹H NMR (400 MHz, CDCl₃) δ 5.86 (t,J=4.5 Hz, 1H), 4.47 (broad, 1H), 2.18 (m, 2H), 1.83-1.43 (m, 7H), 1.32(d, J=5.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 181.91, 96.88, 44.52,40.54, 34.06, 25.28, 22.23.

Example 22: Preparation of 3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one:This reaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of freshly prepared but-1-enemagnesium bromide Grignard reagent (96 mmol, 1M, 3 equiv) in dry ether,3-hydroxy-2-oxaspiro[4.4]nonan-1-one (5.0 g, 32.0 mmol, 1.0 equiv) wasadded dropwise during 0.5 hours at 0° C. The reaction mixture wasstirred overnight at room temperature, quenched with 10% HCl (whilecooling in ice bath) until acidic (pH=2). The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (3×200mL). The extract was washed with 10% NaHCO₃ (100 mL) and brine (200 mL).The solution was then dried over MgSO₄, concentrated in vacuo andpurified by flash column chromatography (silica gel; Ethylacetate/Hexanes, 0%˜25%) to give desired product. ¹H NMR (400 MHz,CDCl₃) δ 5.79 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.15-4.88 (m, 2H), 4.36(ddt, J=9.7, 7.9, 5.5 Hz, 1H), 2.18 (m, 4H), 1.93-1.46 (m, 10H); ¹³C NMR(101 MHz, CDCl₃) δ 182.55, 137.26, 115.62, 77.19, 50.28, 43.24, 37.51,36.91, 34.83, 29.70, 25.56, 25.47.

The following compounds can be prepared by the procedure of3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one. One of ordinary skill inthe art will know how to substitute the appropriate reagents, startingmaterials and purification methods known to those skilled in the art, inorder to prepare the compounds provided herein.

Example 23: Preparation of 3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one, except3-hydroxy-2-oxaspiro[4.5]decan-1-one was substituted for3-hydroxy-2-oxaspiro[4.4]nonan-1-one: ¹H NMR (400 MHz, CDCl₃) δ 5.80(ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.17-4.89 (m, 2H), 4.48-4.31 (m, 1H),2.36 (dd, J=12.9, 6.3 Hz, 1H), 2.30-2.08 (m, 2H), 1.87-1.17 (m, 13H);¹³C NMR (101 MHz, CDCl₃) δ 181.68, 137.31, 115.67, 76.77, 45.04, 39.55,35.31, 34.43, 31.70, 29.75, 25.42, 22.29, 22.22

Example 24: Preparation of 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl4-methylbenzenesulfonate: To a stirred mixture of3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one (0.194 g, 1 mmol, 1 equiv).RuCl₃ stock solution (7.2 mg, 0.035M in water, 0.035 equiv) and CH₃CN (6mL), NaIO₄ (434 mg, 2.04 mmol, 2.04 equiv) was added in portions over aperiod of 5 min at room temperature. The suspension was allowed to stirat room temperature for another 30 min. The reaction was quenched withsaturated aqueous solution of Na₂S₂O₃ and the two layers were separated.The aqueous layer was extracted with ethyl acetate (3×20 mL). Thecombined organic layer was washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated. The crude aldehyde was used for thenext step without further purification.

This reaction was performed in oven-dried glassware under a nitrogenatmosphere. To a well-stirred solution of the crude aldehyde (0.196 g, 1mmol, 1 equiv) in dry methanol, NaBH₄ (74 mg, 2.0 mmol. 2 equiv) wasadded to the mixture in one portion at 0° C. The reaction mixture wasstirred at room temperature for another 1 h, quenched with brine (whilecooling in ice bath). The organic layer was separated and the aqueouslayer was extracted with ethyl acetate (3×20 mL). The combined organicphase was then dried over MgSO₄, concentrated in vacuo. The crudealcohol was used for the next step without further purification.

To a stirred solution of the crude alcohol (0.396 g. 2 mmol, 1.0 equiv)and triethylamine (0.303 g, 3 mmol, 1.5 equiv) in dry dichloromethane, asolution of p-TosCl (0.475 g, 2.5 mmol, 1.25 equiv) in dichloromethanewas added drop wise at 0° C. The resulting mixture was stirred at 0° C.for 1 hour and allowed to stir overnight at room temperature. Then, thereaction mixture was diluted with dichloromethane (50 mL), washed with10% HCl, brine, dried over MgSO₄ and concentrated in vacuo to affordyellowish oil. This crude product was then purified by flashchromatography (silica gel; Ethyl acetate/Hexanes, 0%˜40%) to afforddesired tosylate. ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.71 (m, 2H), 7.35 (m,2H), 4.37-4.23 (m, 1H), 4.06 (qdd, J=10.0, 6.7, 5.2 Hz, 2H), 2.45 (s,3H), 2.15 (m, 2H), 1.92-1.50 (m, 12H); ¹³C NMR (101 MHz, CDCl₃) δ182.29, 145.03, 133.05, 130.04, 128.00, 76.90, 69.91, 50.24, 43.20,37.53, 36.92, 31.74, 25.59, 25.49, 25.37, 21.76.

The following compounds can be prepared by the procedure of3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl 4-methylbenzenesulfonate. Oneof ordinary skill in the art will know how to substitute the appropriatereagents, starting materials and purification methods known to thoseskilled in the art, in order to prepare the compounds provided herein.

Example 25: Preparation of 3-(1-oxo-2-oxaspiro[4.5]decan-3-yl)propyl4-methylbenzenesulfonate: The title compound was prepared according tothe procedure for 3-(1-oxo-2-oxaspiro[4.4]nonan-3-yl)propyl4-methylbenzenesulfonate, except3-(but-3-en-1-yl)-2-oxaspiro[4.5]decan-1-one was substituted for3-(but-3-en-1-yl)-2-oxaspiro[4.4]nonan-1-one: ¹H NMR (400 MHz, CDCl₃) δ7.78 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.39-4.26 (m, 1H),4.16-3.97 (m, 2H), 2.44 (s, 3H), 2.32 (dt, J=15.8, 7.9 Hz, 1H),1.98-1.13 (in, 16H); ¹³C NMR (101 MHz, CDCl₃) δ 181.36, 145.03, 133.05,130.03, 127.99, 76.46, 69.91, 44.97, 39.54, 34.40, 32.15, 31.68, 25.37,25.36, 22.25, 22.18, 21.76

Example 26: Preparation of5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one: To a solution of3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one (8.03 g, 43.0 mmol,I eq.) in tetrahydrofuran (143 mL) was added triphenylphosphine (16.94g, 64.6 mmol, 1.5 eq.). The resulting solution was cooled to 0° C. andcarbon tetrabromide (21.44 g, 64.6 mmol, 1.5 eq.) was added in oneportion. The reaction was allowed to stir at 22° C. overnight. Thereaction mixture was diluted with ether and filtered and concentratedonto Celite in vacuo and further purified by column chromatography(ethyl acetate/hexanes, 0%˜30%, solid load). ¹H NMR (400 MHz, CDCl₃)δ4.60 (m, 1H), 3.53 (dd, J=5.5, 7.6 Hz, 2H), 2.27-2.07 (m, 3H). 1.82(dd, J=9.3, 13.0 Hz, 1H), 1.69-1.57 (m, 4H), 0.93 (dt, J=7.5, 25.7 Hz,6H).

Example 27: Preparation of 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one, except3-(2-hydroxyethyl)-2-oxaspiro[4.5]decan-1-one was substituted for3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one: ¹H NMR (400 MHz,CDCl₃) δ4.61 (in, 1H), 3.53 (dd, J=5.5, 7.6 Hz, 2H), 2.44 (dd, J=6.4,12.9 Hz, 1H), 2.29-2.07 (m, 2H), 1.88-1.70 (m, 3H), 1.69-1.54 (m, 4H),1.53-1.44 (m, 1H), 1.44-1.18 (in, 3H).

Example 28: Preparation of5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:A solution of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.400g, 1.53 mmol, 1 eq.), acetonitrile (8 mL),2-benzyloctahydropyrrolo[3,4-c]pyrrole (0.340 g, 1.68 mmol, 1.1 eq.) andK₂CO₃ (1.05 g, 7.65 mmol, 5 eq.) was heated and stirred at 80° C. for 24hours. The resulting mixture was then filtered and concentrated in vacuoto give a crude residue that was further purified by columnchromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz,CDCl₃) δ7.25-7.14 (m, 4H), 7.14-7.06 (m, 1H), 4.38 (m, 1H), 3.46 (s,2H), 2.64-2.48 (m, 6H), 2.48-2.38 (m, 2H), 2.28-2.13 (m, 4H), 2.02 (dd,J=6.8, 13.0 Hz, 1H), 1.87-1.59 (m, 3H), 1.58-1.44 (m, 4H), 0.83 (dt,J=7.3, 21.4 Hz, 6H); MS (LC/MS, M+H⁺): m/z 371.2

Example 29: Preparation of3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one,except 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one was substituted for5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one: ¹H NMR (400 MHz,CDCl₃) δ7.26-7.17 (m, 4H), 7.17-7.10 (m, 1H), 4.40 (m, 1H), 3.50 (s,2H), 2.69-2.52 (m, 6H), 2.49 (t, J=7.4 Hz, 2H), 2.30 (dd, J=6.3, 12.8Hz, 1H), 2.27-2.16 (m, 4H), 1.88-1.61 (m, 5H), 1.61-1.45 (m, 4H),1.44-1.37 (m, 1H), 1.36-1.07 (m, 3H); MS (LC/MS, M+H⁺): m/z 383.2

Example 30: Preparation of3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:A mixture of5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one(540 mg, 1.46 mmol, 1 eq.), Pd/C (108 mg, 20% wt) and MeOH (5.0 mL) wasstirred at 22° C. under 1 atm of H₂ (filled balloon) for 3 days. Themixture was filtered through a plug of Celite, washed with MeOH (50 mL)and concentrated in vacuo to give a crude product that was used infollowing steps without further purification. ¹H NMR (400 MHz, CDCl₃)δ4.42 (m, 1H), 2.83 (b, 1H), 2.69 (m, 2H), 2.55-2.39 (m, 4H), 2.33 (m,2H), 2.26 (t, J=7.0 Hz, 2H), 2.14 (dd, J=1.7, 9.0 Hz, 2H), 1.91 (dd,J=6.7, 13.0 Hz, 1H), 1.71-1.47 (m, 3H), 1.45-1.32 (m, 4H), 0.69 (dt,J=7.4, 19.2 Hz, 6H); MS (LC/MS, M+H⁺): m/z 281.2.

Example 31: Preparation of3-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except3-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-onewas substituted for5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:¹H NMR (400 MHz, CDCl₃) δ4.55 (m, 1H), 2.94 (m, 2H), 2.82-2.63 (m, 5H),2.63-2.46 (m, 3H), 2.42 (m, 2H), 1.97-1.60 (m, 8H), 1.59-1.43 (m, 3H),1.43-1.22 (m, 4H); MS (LC/MS, M+H⁺): m/z 293.2

Example 32: Preparation of 1-(benzyloxy)-2-bromobenzene: To a solutionof 2-bromophenol (1.0 g, 5.78 mmol, 1.01 eq.) in acetonitrile (14 mL)was added benzyl bromide (0.975 g, 5.7 mmol. 1.0 eq.) and K₂CO₃ (1.09 g,7.87 mmol, 1.38 eq.). This mixture was allowed to stir at 22° C.overnight. The reaction was filtered and concentrated in vacuo to give acrude residue that was further purified by column chromatography(hexanes/ethyl acetate, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ7.60 (dd,J=1.6, 7.8 Hz, 1H), 7.51 (m, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.35 (m, 1H),7.29-7.22 (m, 1H), 6.97 (dd, J=1.2 8.3 Hz, 1H), 6.88 (td, J=1.3, 7.6 Hz,1H), 5.19 (s, 2H).

Example 33: Preparation of 1-(benzyloxy)-3-bromobenzene: The titlecompound was prepared according to the procedure for1-(benzyloxy)-2-bromobenzene, except 3-bromophenol was substituted for2-bromophenol: ¹H NMR (400 MHz, CDCl₃) δ7.50-7.34 (m, 5H), 7.23-7.10 (m,3H), 6.95 (m, 1H), 5.08 (s, 2H).

Example 34: Preparation of 1-(benzyloxy)-4-bromobenzene: The titlecompound was prepared according to the procedure for1-(benzyloxy)-2-bromobenzene, except 4-bromophenol was substituted for2-bromophenol: ¹H NMR (400 MHz, CDCl₃) δ7.51-7.33 (m, 7H), 6.91 (d,J=9.1 Hz, 2H), 5.08 (s, 2H).

Example 35: Preparation of 4-(2-bromophenyl)morpholine: This reactionwas performed in oven-dried glassware under a nitrogen atmosphere. To asolution of 1,2-dibromobenzene (1.0 g, 4.24 mmol, 1.0 eq.) andmorpholine (0.370 g. 4.24 mmol, 1.0 eq.) in anhydrous toluene (10.6 mL)was added the following in this order: Pd₂(dba)₃ (0.097 g, 5 mol %),BINAP (0.197 g, 7.5 mol %), and NaOtBu (0.448 g, 5.08 mmol, 1.2 eq.).The resulting mixture was allowed to stir at 80° C. overnight, under asweep of N₂. The reaction mixture was cooled to 22° C. and then filteredthrough a plug of Celite. The collected filtrate was concentrated invacuo to give a crude residue that was further purified by columnchromatography (hexanes/ethyl acetate, 0%˜20%). ¹H NMR (400 MHz, CDCl₃)δ7.55 (dd, J=1.5, 7.9 Hz. 1H), 7.25 (td, J=1.4, 7.8 Hz, 1H), 7.00 (dd,J=1.4, 8.0 Hz, 1H), 6.89 (td, J=1.4, 7.7 Hz, 1H), 3.83 (m, 4H), 2.99 (m,4H); MS (LC/MS, M+H⁺): m/z 241.9, 243.8.

Example 36: Preparation of tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-2-methylbenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.18-7.10 (m, 2H), 6.96-6.89 (m,2H), 3.69 (b, 2H), 3.36 (b, 2H), 3.18 (b, 2H), 3.05 (b, 2H), 2.91 (b,2H), 2.33 (s, 3H), 1.52 (s, 9H); MS (LC/MS, M+H⁺): m/z 303.2

Example 37: Preparation of tert-butyl5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-3-methylbenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.17 (t, J=7.8 Hz, 1H), 6.59 (d,J=7.5 Hz, 1H), 6.46-6.37 (m, 2H), 3.68 (b, 2H), 3.52 (b, 2H), 3.42 (m,1H), 3.29 (m, 1H), 3.23 (m, 2H), 2.97 (b, 2H), 2.38 (s. 3H), 1.54 (s,9H); MS (LC/MS, M+H⁺): m/z 303.2

Example 38: Preparation of tert-butyl5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-4-methylbenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.09 (d, J=8.1 Hz, 2H), 6.52 (d,J=8.5 Hz, 2H), 3.68 (m, 2H), 3.57 (b, 2H), 3.42 (m, 1H), 3.28 (m, 1H),3.21 (m, 2H), 3.00 (b, 2H), 2.30 (s, 3H), 1.51 (s. 9H); MS (LC/MS,M+H⁺): m/z 303.2.

Example 39: Preparation of tert-butyl5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-2-methoxybenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ6.91-6.78 (m, 3H), 6.76-6.67 (m,1H), 3.80 (s, 3H), 3.61 (b. 2H), 3.45 (b, 2H), 3.40-3.22 (m, 2H), 3.14(b, 2H), 2.90 (b, 2H), 1.46 (s, 9H); MS (LC/MS, M+H⁺): m/z 319.2.

Example 40: Preparation of tert-butyl5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-3-methoxybenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.13 (t, J=8.1 Hz, 1H), 6.29 (dd,J=2.2, 8.1 Hz, 1H), 6.18 (dd. J=1.8, 8.1 Hz, 1H), 6.10 (t, J=2.2 Hz,1H), 3.79 (s, 3H), 3.63 (m, 2H), 3.50 (m, 2H). 3.37 (m, 1H), 3.30-3.11(m, 3H), 2.95 (b, 2H), 1.48 (s, 9H); MS (LC/MS, M+H⁺): m/z 319.2

Example 41: Preparation of tert-butyl5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-4-methoxybenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ6.83 (d, J=9.0 Hz, 2H), 6.50 (d,J=9.0 Hz, 2H), 3.73 (s, 3H), 3.62 (m, 2H), 3.48-3.29 (m, 3H), 3.23 (m,1H), 3.12 (dd, J=3.5, 9.3 Hz, 2H), 2.93 (b, 2H), 1.46 (s, 9H); MS(LC/MS, M+H⁺): m/z 319.2.

Example 42: Preparation of tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 2-bromobenzonitrile was substituted for bromobenzene: ¹HNMR (400 MHz, CDCl₃) δ7.39 (dd, J=1.6, 7.8 Hz, 1H), 7.30 (m, 1H), 6.66(t, J=7.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 2H),3.52 (m, 1H), 3.44 (m, 1H), 3.28 (m, 2H), 2.95 (b, 2H), 1.42 (s, 9H); MS(LC/MS. M+H⁺): m/z 314.2.

Example 43: Preparation of tert-butyl5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 3-bromobenzonitrile was substituted for bromobenzene: ¹HNMR (400 MHz, CDCl₃) δ7.22 (m, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.71-6.64(m, 2H), 3.62 (m, 2H), 3.49 (m, 2H), 3.31 (m, 1H), 3.23 (m, 1H), 3.16(dd, J=3.9, 9.7 Hz, 2H), 2.99 (b, 2H), 1.42 (s, 9H); MS (LC/MS, M+H⁺):m/z 314.2

Example 44: Preparation of tert-butyl5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: Thetitle compound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 4-bromobenzonitrile was substituted for bromobenzene: ¹HNMR (400 MHz, CDCl₃) δ7.35 (d. J=8.9 Hz, 2H), 6.41 (d, J=8.9 Hz, 2H),3.57 (m, 2H), 3.50 (m, 2H), 3.26 (in, 1H), 3.21-3.06 (m, 3H), 2.95 (b,2H), 1.37 (s, 9H); MS (LC/MS, M+H⁺): m/z 314.2.

Example 45: Preparation of tert-butyl5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 1-(benzyloxy)-2-bromobenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.36-7.23 (m, 4H), 7.20 (m, 111),6.79 (m, 2H), 6.72 (m, 1H), 6.65 (m, 1H), 4.94 (s, 2H), 3.50 (b, 2H),3.33 (m, 2H), 3.27-3.02 (m, 3H), 2.76 (b, 2H), 1.35 (s, 9H); MS (LC/MS,M+H⁺): m/z 395.2.

Example 46: Preparation of tert-butyl5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 1-(benzyloxy)-3-bromobenzene was substituted forbromobenzene: ¹H NMR (400 MHz. CDCl₃) δ7.47 (m, 2H), 7.41 (t, J=7.6 Hz,2H), 7.34 (m, 1H), 7.17 (t, J=8.2 Hz, 1H), 6.39 (dd, J=1.7, 8.0 Hz, 1H),6.23 (m, 2H), 5.08 (s, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.40 (m, 1H),3.33-3.14 (m, 3H), 2.99 (b, 2H), 1.49 (s, 9H); MS (LC/MS, M+H⁺): m/z395.2.

Example 47: Preparation of tert-butyl5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 1-(benzyloxy)-4-bromobenzene was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.46 (m, 2H), 7.40 (t, J=7.8 Hz,2H), 7.34 (m, 1H), 6.95 (d, J=9.0 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 5.03(s, 2H), 3.67 (b, 2H), 3.47 (b, 2H), 3.40 (m, 1H), 3.28 (m, 1H), 3.18(dd, J=3.4, 9.3 Hz, 2H), 2.99 (b, 2H), 1.50 (s, 9H); MS (LC/MS, M+H):m/z 395.2.

Example 48: Preparation of tert-butyl5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:The title compound was prepared according to the procedure fortert-butyl 6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, excepttert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylester hemioxylate and 4-(2-bromophenyl)morpholine was substituted forbromobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.04-6.89 (m, 3H), 6.85 (d, J=7.8Hz, 1H), 3.85 (t, J=4.5 Hz, 4H), 3.62 (b, 2H), 3.48-3.21 (m, 6H), 3.04(t, J=4.5 Hz, 4H), 2.92 (b, 2H), 1.48 (s, 9H); MS (LC/MS, M+H): m/z374.2.

Example 49: Preparation of2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: The titlecompound was prepared according to the procedure for tert-butyl6-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxylate, except2-benzyloctahydropyrrolo[3,4-c]pyrrole was substituted for2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl esterhemioxylate and 1-bromo-2-isopropylbenzene was substituted forbromobenzene. The product was purified by column chromatography(dichloromethane/MeOH, 0%˜5%). ¹H NMR (400 MHz, CDCl₃) δ7.54-7.33 (m,6H), 7.32-7.11 (m, 3H), 3.77 (s, 2H), 3.65 (sept, J=6.9 Hz, 1H), 3.15(m, 2H), 3.09-2.99 (m, 4H), 2.96 (m, 2H), 2.47 (dd, J=4.9, 8.8 Hz, 2H),1.39 (d, J=6.9 Hz, 9H); MS (LC/MS, M+H⁺): m/z 321.2.

Example 50: Preparation of 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: Toa solution of tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.490 g,1.62 mmol, 1 eq.) in dichloromethane (4 mL) at 0° C. was addedtrifluoroacetic acid (2 mL). The reaction was allowed to stir at 22° C.for 30 minutes before being diluted with McOH and concentrated in vacuoto afford the product as a TFA salt. The salt was then suspended in sat.NaHCO₃ solution and the free based product was extracted with methylenechloride (3×15 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentration in vacuo to afford the product as a freebase: MS (LC/MS, M+H⁺): m/z 203.2.

Example 51: Preparation of 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole:The title compound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 203.2.

Example 52: Preparation of 2-(p-tolyl)octahydropyrrolo[3,4-c]pyrrole:The title compound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 203.2

Example 53: Preparation of2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: The title compoundwas prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 219.2.

Example 54: Preparation of2-(4-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole: The title compoundwas prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxy late: MS (LC/MS,M+H⁺): m/z 219.2.

Example 55: Preparation of3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: The titlecompound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 214.2

Example 56: Preparation of4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile: The titlecompound was prepared according to the procedure for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole, except tert-butyl5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS (LC/MS,M+H⁺): m/z 214.2.

Example 57: Preparation of2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride: Toa solution of tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.408g, 1.30 mmol, 1 eq.) in MeOH (1 mL) at 0° C. was added 1M methanolic HCl(3 mL). The reaction was allowed to stir at 22° C. overnight beforebeing diluted with MeOH and concentrated in vacuo to afford the productas a HCl salt. MS (LC/MS, M+H⁺): m/z 214.2.

Example 58: Preparation of2-(3-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate wassubstituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS. M+H⁺): m/z 219.2.

Example 59: Preparation of2-(2-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS, M+H⁺): m/z 295.2.

Example 60: Preparation of2-(3-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS. M+H⁺): m/z 295.2.

Example 61: Preparation of2-(4-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride: Thetitle compound was prepared according to the procedure for2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile hydrochloride,except tert-butyl5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS, M+H⁺): m/z 295.2.

Example 62: Preparation of4-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)morpholinehydrochloride: The title compound was prepared according to theprocedure for 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrilehydrochloride, except tert-butyl5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas substituted for tert-butyl5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: MS(LC/MS. M+H⁺): m/z 274.2.

Example 63: Preparation of2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole: To a dry roundbottom flask, 0.04 g of 10% Pd/C (20% wt) was added and wet with a smallamount of ethyl acetate. Following, a solution of2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole (0.20 g,0.624 mmol, 1 eq.) in MeOH (2.1 mL) was added slowly to the Pd/Ccontaining round bottom flask. This system was then flushed 3× with H2,using a balloon filled with H₂. The reaction was allowed to stir under 1atm H2 for 5 days at room temperature. The Pd/C was removed viafiltration through a plug of Celite. The filtrate was concentrated invacuo to afford a crude oil of2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole which was used inthe next step without further purification. MS (LC/MS, M+H⁺): m/z 231.2.

Example 64: Preparation of3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole wassubstituted for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate: ¹HNMR (400 MHz, CDCl₃) δ7.18 (dd, J=1.5, 7.4 Hz, 1H), 7.10-6.90 (m, 3H),4.43 (m, 1H), 3.38 (sept, J=6.9 Hz, 1H), 3.01-2.84 (m, 4H), 2.83-2.66(m, 4H), 2.52 (t, J=6.8 Hz, 2H), 2.19 (m, 2H), 2.06 (dd, J=6.8, 13.1 Hz,1H), 1.91-1.67 (m, 3H), 1.63-1.44 (m, 4H), 1.15 (d, J=6.9 Hz, 6H), 0.86(dt, J=7.3, 19.3 Hz, 6H); MS (LC/MS, M+H⁺): m/z 399.2.

Example 65: Preparation of3-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxaspiro[4.5]decan-1-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one,except 3-(2-bromoethyl)-2-oxaspiro[4.5]decan-1-one was substituted for5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one and2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole was substituted for2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate: ¹H NMR (400 MHz,CDCl₃) δ7.18 (dd, J=1.5, 7.0 Hz, 1H), 7.09-6.94 (m, 3H), 4.44 (m, 1H),3.37 (sept, J=6.8 Hz, 1H), 2.99-2.83 (m, 4H), 2.82-2.66 (m, 4H), 2.52(t, J=7.2 Hz, 2H), 2.32 (dd, J=6.3, 12.7 Hz, 1H), 2.24-2.12 (m, 2H),1.93-1.81 (m, 1H), 1.80-1.46 (m, 8H), 1.46-1.37 (m, 1H), 1.37-1.04 (m,9H) MS (LC/MS, M+H⁺): m/z 411.2.

Example 66: Preparation of3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:A mixture of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.075g, 0.301 mmol, 1 eq.), acetonitrile (3 mL),2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole (0.073 g, 0.361 mmol, 1.2 eq.)and N,N-diisopropylethyl amine (0.116 g, 0.903 mmol, 3 eq.) wasmicrowaved at 120° C. for 4 hrs. The resulting solution was concentratedin vacuo to give a crude residue that was first purified by columnchromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz,CDCl₃) δ7.15 (m, 2H), 6.96 (m, 2H), 4.50 (m, 1H), 3.08-2.92 (m, 6H),2.86 (b, 2H), 2.60 (t, J=6.9 Hz, 2H). 2.37-2.24 (m, 5H), 2.14 (dd,J=6.7, 13.0 Hz, 1H), 1.99-1.75 (m, 3H), 1.64 (m, 4H), 0.94 (dt, J=7.4,18.1 Hz, 6H); MS (LC/MS, M+H⁺): m/z 371.2.

Example 67: Preparation of3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃) δ7.13(t, J=8.0 Hz, 1H), 6.58 (d, J=7.4 Hz. 1H), 6.53-6.45 (m, 2H), 4.47 (m,1H), 3.37 (m, 2H), 3.18 (dt, J=2.8, 9.4 Hz, 2H), 2.95 (b, 2H), 2.86 (m,2H), 2.59 (t, J=7.0 Hz, 2H), 2.41 (dd, J=4.0, 8.9 Hz, 2H), 2.33 (s, 3H),2.12 (dd, J=6.6, 13.0 Hz, 1H). 1.97-1.73 (m, 3H), 1.62 (q, J=7.5 Hz,4H), 0.92 (dt, J=7.5, 14.8 Hz, 6H); MS (LC/MS, M+^(H)): m/z 371.2.

Example 68: Preparation of3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(p-tolyl)octahydropyrrolo[3,4-c]pyrrole was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃) δ6.89(d, J=8.4 Hz, 2H), 6.45 (d, J=8.4 Hz, 2H), 4.32 (m, 1H), 3.17 (m, 2H),2.99 (dt, J=3.0, 9.2 Hz, 2H), 2.78 (b, 2H), 2.70 (m, 2H), 2.42 (t, J=6.9Hz, 2H), 2.42 (dd, J=4.0, 8.8 Hz. 2H), 2.11 (s, 3H), 2.97 (dd, J=6.8,13.0 Hz, 1H), 1.81-1.57 (m, 3H), 1.45 (q, J=7.2 Hz, 4H), 0.76 (dt,J=7.5, 14.7 Hz, 6H); MS (LC/MS, M+H⁺): m/z 371.2.

Example 69: Preparation of2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrilehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃) δ7.45(dd, J=1.5, 7.6 Hz, 1H), 7.36 (m, 1H). 6.81-6.68 (m, 2H), 4.45 (m, 1H),3.62 (m, 2H), 3.45 (td, J=2.0, 8.6 Hz, 2H), 2.92 (b, 2H), 2.74 (m, 2H),2.63-2.53 (m, 2H), 2.52-2.46 (m, 2H), 2.11 (dd, J=6.8, 13.0 Hz, 1H),1.94-1.70 (m, 3H), 1.58 (qd, J=2.6, 7.4 Hz, 4H), 0.88 (dt, J=7.3, 14.8Hz, 6H); MS (LC/MS, M+H⁺): m/z 382.2.

Example 70: Preparation of3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile wassubstituted for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400MHz, CDCl₃) δ7.26 (m, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.82-6.75 (m, 2H),4.44 (m, 1H), 3.44 (t, J=8.7 Hz, 2H), 3.15 (dt, J=3.8. 9.4 Hz, 2H), 2.98(b, 2H), 2.73 (m, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.50 (dd, J=3. 1, 9.1 Hz,2H), 2.10 (dd, J=6.8, 12.9 Hz, 1H). 1.94-1.70 (m, 3H), 1.59 (q, J=7.3Hz, 4H), 0.89 (dt, J=5.4, 14.9 Hz, 6H); MS (LC/MS, M+H): m/z 382.2.

Example 71: Preparation of4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile wassubstituted for 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400MHz, CDCl₃) δ7.44 (d, J=8.9 Hz, 2H), 6.54 (d, J=8.7 Hz, 2H), 4.44 (m,1H), 3.55 (t, J=9.0 Hz, 2H), 3.23 (dt, J=3.6, 9.9 Hz, 2H), 3.00 (b, 2H),2.72 (m, 2H), 2.64-2.50 (m, 4H), 2.10 (dd, J=6.7, 13.1 Hz, 1H).1.94-1.71 (m, 3H), 1.59 (q, J=7.5 Hz, 4H), 0.89 (dt, J=5.1, 14.9 Hz,6H); MS (LC/MS, M+H⁺): m/z 382.2.

Example 72: Preparation of3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was substitutedfor 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ6.83-6.61 (m, 4H), 4.34 (m, 1H), 3.71 (s, 3H), 3.23 (q, J=7.5 Hz, 2H),2.86 (m, 2H), 2.72 (b, 2H), 2.58 (b, 2H), 2.44 (m, 2H), 2.31 (dt, J=3.2,8.8 Hz, 2H), 1.98 (dd, J=6.8, 13.1 Hz, 1H), 1.84-1.73 (m, 1H), 1.73-1.58(m, 2H), 1.47 (qd, J=1.5, 7.5 Hz, 4H), 0.77 (dt, J=7.3, 15.8 Hz, 6H); MS(LC/MS, M+H⁺): m/z 387.2.

Example 73: Preparation of3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(3-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was substitutedfor 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.14 (t, J=8.2 Hz, 1H), 6.30 (m. 2H), 6.20 (t, J=2.2 Hz, 1H), 4.46 (m,1H), 3.79 (s, 3H), 3.38 (t, J=8.2 Hz, 2H), 3.17 (dt, J=3.0, 9.5 Hz, 2H),2.94 (b, 2H), 2.86-2.77 (m, 2H), 2.57 (t, J=7.1 Hz, 2H), 2.42 (dd,J=3.9, 9.0 Hz, 2H), 2.11 (dd, J=6.8, 13.0 Hz, 1H), 1.95-1.72 (m, 3H),1.61 (qd, J=1.5, 7.5 Hz, 4H), 0.91 (dt, J=7.4, 14.8 Hz, 6H); MS (LC/MS,M+H⁺): m/z 387.2.

Example 74: Preparation of3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(4-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole was substitutedfor 2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ6.83 (d, J=9.0 Hz, 2H), 6.65 (d, J=9.0 Hz, 2H), 4.46 (m, 1H), 3.76 (s,3H), 3.28 (m, 2H), 3.10 (dt, J=3.2, 9.1 Hz, 2H), 2.92 (b, 2H), 2.84 (b,2H), 2.63-2.51 (m, 2H), 2.39 (dd, J=4.0, 8.7 Hz, 2H), 2.11 (dd, J=6.8,13.0 Hz, 1H), 1.97-1.71 (m, 3H), 1.61 (qd, J=1.3, 7.4 Hz, 4H), 0.91 (dt,J=7.3, 14.8 Hz, 6H); MS (LC/MS, M+H⁺): m/z 387.2.

Example 75: Preparation of3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 4-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)morpholinehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.05-6.94 (m, 3H), 6.91-6.83 (m, 1H), 4.49 (m, 1H) 3.85 (t, J=4.7 Hz,4H), 3.68-3.42 (m, 4H), 3.22-2.84 (m, 10H), 2.61 (b, 2H), 2.30 (b, 1H).2.19 (dd, J=6.7, 13.2 Hz, 1H). 2.05-1.90 (m, 1H), 1.84 (dd, J=9.3, 13.2Hz, 1H), 1.67-1.56 (m, 4H), 0.91 (dt, J=7.3, 16.5 Hz, 6H); MS (LC/MS,M+H⁺): m/z 442.2.

Example 76: Preparation of5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(2-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrolehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.46-7.29 (m, 5H), 7.01-6.86 (m, 3H), 6.81 (dd, J=1.4, 7.7 Hz, 1H),5.03 (s, 2H), 4.43 (m, 1H), 3.61 (b, 2H), 3.36 (t, J=10.6 Hz, 2H),3.17-2.97 (m, 3H), 2.91 (td, J=5.3, 12.2 Hz, 1H), 2.86-2.73 (m, 2H),2.58-2.37 (m, 2H), 2.30 (m, 1H), 2.17 (dd, J=6.7, 13.1 Hz, 1H),1.92-1.73 (m, 2H), 1.61 (q. J=7.4 Hz, 4H), 0.91 (dt, J=7.0, 13.9 Hz,6H); MS (LC/MS, M+H⁺): m/z 463.2.

Example 78: Preparation of5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(3-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrolehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.39-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.26-7.20 (m, 1H), 7.05 (m, 1H),6.29 (dd, J=1.7, 8.1 Hz, 1H), 6.24-6.18 (m, 2H), 4.96 (s, 2H), 4.37 (m,1H), 3.28 (m, 2H), 3.08 (dt, J=2.9, 9.3 Hz, 2H), 2.93-2.81 (m, 2H),2.81-2.69 (m, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.33 (dd, J 3.9, 8.9 Hz, 2H),2.02 (dd, J=6.7, 13.0 Hz, 1H), 1.87-1.63 (m, 3H), 1.52 (qd, J=1.2, 7.4Hz, 4H), 0.82 (dt, J=7.4, 14.9 Hz, 6H); MS (LC/MS, M+H⁺): m/z 463.2.

Example 79: Preparation of5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except 2-(4-(benzyloxy)phenyl)octahydropyrrolo[3,4-c]pyrrolehydrochloride was substituted for2-(o-tolyl)octahydropyrrolo[3,4-c]pyrrole: ¹H NMR (400 MHz, CDCl₃)δ7.37-7.31 (m, 2H), 7.31-7.25 (m, 2H), 7.24-7.18 (m, 1H), 6.81 (d, J=9.0Hz, 2H), 6.55 (d, J=9.0 Hz, 2H), 4.92 (s, 2H), 4.37 (m, 1H), 3.19 (m,2H), 3.01 (dt, J=3.1, 9.3 Hz, 2H), 2.89-2.80 (m, 2H), 2.80-2.70 (m, 2H),2.48 (t, J=6.9 Hz, 2H), 2.29 (dd, J 3.9, 8.6 Hz, 2H), 2.02 (dd, J=6.7,13.1 Hz, 1H), 1.87-1.62 (m, 3H), 1.52 (q, J=7.3 Hz, 4H), 0.82 (dt,J=7.5, 14.5 Hz, 6H); MS (LC/MS, M+H⁺): m/z 463.2.

Example 80: Preparation of3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:To a dry RBF, 0.013 g of 10% Pd/C (20% wt) was added and wet with asmall amount of ethyl acetate. Following, a solution of5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one(0.065 g, 0.140 mmol, 1 eq.) in MeOH (1.5 mL) was added slowly to thePd/C containing RBF. This system was then flushed 3× with H₂, using aballoon filled with H₂. The reaction was allowed to stir under 1 atm H₂for overnight at room temperature. The Pd/C was removed via filtrationthrough a plug of Celite. The filtrate was concentrated in vacuo to givea crude residue that was first purified by column chromatography(methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ7.13 (dd,J=1.3. 7.8 Hz, 1H), 7.05 (td, J=1.3, 7.7 Hz, 1H), 6.93 (dd, J=1.3, 8.1Hz, 1H), 6.85 (td, J=1.4, 7.7 Hz, 1H), 4.52 (m, 1H), 3.12-3.00 (m, 2H),2.98-2.74 (m, 6H), 2.65 (t, J=7.3 Hz. 2H), 2.58-2.46 (m, 2H), 2.16 (dd,J=6.7, 13.1 Hz. 1H), 2.00-1.76 (m, 3H), 1.64 (q, J=7.5 Hz, 4H), 0.95(dt, J=7.4, 22.8 Hz, 6H); MS (LC/MS, M+H⁺): m/z 373.2.

Example 81: Preparation of3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-onewas substituted for5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one:¹H NMR (400 MHz. CDCl₃) δ6.85 (t, J=8.1 Hz, 1H), 6.00 (td, J=1.8, 7.6Hz, 2H), 5.91 (t, J=2.3 Hz, 1H), 4.24 (m, 1H), 3.18-3.05 (m, 2H), 2.97(d, J=9.2 Hz, 2H), 2.83-2.64 (m, 4H), 2.44 (t, J=7.3 Hz, 2H), 2.25 (m,2H), 1.91 (dd, J=6.7, 13.1 Hz, 1H), 1.77-1.53 (m, 3H), 1.40 (q, J=7.4Hz, 4H), 0.70 (dt, J=7.4. 15.6 Hz, 6H); MS (LC/MS, M+H⁺): m/z 373.2.

Example 82: Preparation of3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-onetrifluoroacetate: The title compound was prepared according to theprocedure for3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one,except5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-onewas substituted for5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-oneand the reaction time was extended to 3 days. A second purification wasneed via column chromatography on a C18 column. (acetonitrile/H₂O,0%-100%, w/0.1% TFA): ¹H NMR (400 MHz, MeOD) δ6.78-6.67 (m, 4H), 4.54(m, 1H), 3.69 (b, 2H), 3.45 (dd, J=7.2, 9.6 Hz, 2H), 3.40-3.09 (m, 6H),2.98 (m. 2H), 2.28 (dd, J=6.7, 13.2 Hz, 1H), 2.20-1.97 (m, 2H), 1.91(dd, J=9.4, 13.2 Hz, 1H), 1.74-1.52 (m, 4H), 0.94 (dt, J=5.0, 14.9 Hz,6H); MS (LC/MS, M+H⁺): m/z 373.2.

Example 83: Preparation of3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one:The title compound was prepared according to the procedure for3,3-diethyl-5-(2-(6-phenyl-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)dihydrofuran-2(3H)-one,except 2-phenyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride wassubstituted for 2-phenyl-2,6-diazaspiro[3.3]heptane trifluoroacetate: ¹HNMR (400 MHz, CDCl₃) δ7.14 (m, 2H), 6.64 (t, J=7.2 Hz, 1H), 6.57 (d,J=8.5 Hz, 2H), 4.37 (m, 1H), 3.29 (t, J=8.1 Hz, 2H), 3.08 (dt, J=2.7,9.3 Hz, 2H), 2.92-2.79 (b, 2H), 2.78-2.65 (m, 2H), 2.47 (t, J=6.9 Hz,2H), 2.32 (dd, J=4.0, 8.9 Hz, 2H), 2.02 (dd, J=6.7, 13.1 Hz, 1H),1.87-1.61 (m, 3H), 1.51 (q, J=7.3 Hz. 4H), 0.81 (dt, J=7.5, 13.9 Hz,6H); MS (LC/MS, M+H^(t)): m/z 357.2

Formulations

The present invention also relates to compositions or formulations whichcomprise the 5-hydroxytryptamine receptor 7 activity modulatorsaccording to the present invention. In general, the compositions of thepresent invention comprise an effective amount of one or more compoundsof the disclosure and salts thereof according to the present inventionwhich are effective for providing modulation of 5-hydroxytryptaminereceptor 7 activity; and one or more excipients.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present invention have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

The present teachings also provide pharmaceutical compositions thatinclude at least one compound described herein and one or morepharmaceutically acceptable carriers, excipients, or diluents. Examplesof such carriers are well known to those skilled in the art and can beprepared in accordance with acceptable pharmaceutical procedures, suchas, for example, those described in Remington's Pharmaceutical Sciences,17^(th) edition, ed. Alfonoso R. Gennaro, Mack Publishing Company,Easton, Pa. (1985), the entire disclosure of which is incorporated byreference herein for all purposes. As used herein, “pharmaceuticallyacceptable” refers to a substance that is acceptable for use inpharmaceutical applications from a toxicological perspective and doesnot adversely interact with the active ingredient. Accordingly,pharmaceutically acceptable carriers are those that are compatible withthe other ingredients in the formulation and are biologicallyacceptable. Supplementary active ingredients can also be incorporatedinto the pharmaceutical compositions.

Compounds of the present teachings can be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich can also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents, or encapsulating materials. The compoundscan be formulated in conventional manner, for example, in a mannersimilar to that used for known 5-hydroxytryptamine receptor 7 activitymodulators. Oral formulations containing a compound disclosed herein cancomprise any conventionally used oral form, including tablets, capsules,buccal forms, troches, lozenges and oral liquids, suspensions orsolutions. In powders, the carrier can be a finely divided solid, whichis an admixture with a finely divided compound. In tablets, a compounddisclosed herein can be mixed with a carrier having the necessarycompression properties in suitable proportions and compacted in theshape and size desired. The powders and tablets can contain up to 99% ofthe compound.

Capsules can contain mixtures of one or more compound(s) disclosedherein with inert filler(s) and/or diluent(s) such as pharmaceuticallyacceptable starches (e.g., corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses (e.g., crystalline andmicrocrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine. Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials, ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited to,metered dose inhalers, breath-operated inhalers, multidose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can beformulated into a liquid composition, a solid composition, or an aerosolcomposition. The liquid composition can include, by way of illustration,one or more compounds of the present teachings dissolved, partiallydissolved, or suspended in one or more pharmaceutically acceptablesolvents and can be administered by, for example, a pump or asqueeze-actuated nebulized spray dispenser. The solvents can be, forexample, isotonic saline or bacteriostatic water. The solid compositioncan be, by way of illustration, a powder preparation including one ormore compounds of the present teachings intermixed with lactose or otherinert powders that are acceptable for intrabronchial use, and can beadministered by, for example, an aerosol dispenser or a device thatbreaks or punctures a capsule encasing the solid composition anddelivers the solid composition for inhalation. The aerosol compositioncan include, by way of illustration, one or more compounds of thepresent teachings, propellants, surfactants, and co-solvents, and can beadministered by, for example, a metered device. The propellants can be achlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or otherpropellants that are physiologically and environmentally acceptable.]

Compounds described herein can be administered parenterally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitably mixed with a surfactant such ashydroxyl-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can sterile and its viscositypermits it to flow through a syringe. The form preferably is stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature.

Compounds described herein can be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations can bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polyethylene glycolsof various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings includingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more compounds ofthe disclosure according to the present invention and one or moreexcipients; from about 0.01 mg to about 100 mg of one or more compoundsof the disclosure according to the present invention and one or moreexcipients; and from about 0.1 mg to about 10 mg of one or morecompounds of the disclosure according to the present invention; and oneor more excipients.

Procedures

The following procedures can be utilized in evaluating and selectingcompounds as 5-hydroxytryptamine receptor 7 activity modulators.

Radiolabel Binding Studies for Serotonin 5HT7 Receptors, Method 1:

A solution of the compound of the disclosure to be tested is prepared asa 1-mg/ml stock in Assay Buffer or DMSO according to its solubility. Asimilar stock of the reference compound chlorpromazine is also preparedas a positive control. Eleven dilutions (5× assay concentration) of thecompound of the disclosure and chlorpromazine are prepared in the AssayBuffer by serial dilution to yield final corresponding assayconcentrations ranging from 10 pM to 10 μM.

A stock concentration of 5 nM [³H]LSD (lysergic acid diethyl amide) isprepared in 50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EDTA, pH 7.4 (AssayBuffer). Aliquots (50 d) of radioligand are dispensed into the wells ofa 96-well plate containing 100 μl of Assay Buffer. Duplicate 50-μlaliquots of the compound of the disclosure test and chlorpromazinepositive control reference compound serial dilutions are added.

Membrane fractions of cells expressing recombinant 5HT₇ receptors (50μL) are dispensed into each well. The membranes are prepared from stablytransfected cell lines expressing 5HT₇ receptors cultured on 10-cmplates by harvesting PBS-rinsed monolayers, resuspending and lysing inchilled, hypotonic 50 mM Tris-HCl, pH 7.4, centrifuging at 20,000×g,decanting the supernatant and storing at −80° C.; the membranepreparations are resuspended in 3 ml of chilled Assay Buffer andhomogenized by several passages through a 26 gauge needle before usingin the assay.

The 250-μl reactions are incubated at room temperature for 1.5 hours,then harvested by rapid filtration onto 0.3% polyethyleneimine-treated,96-well filter mats using a 96-well Filtermate harvester. Four rapid500-μl washes are performed with chilled Assay Buffer to reducenon-specific binding. The filter mats are dried, then scintillant isadded to the filters and the radioactivity retained on the filters iscounted in a Microbeta scintillation counter.

Raw data (dpm) representing total radioligand binding (i.e.,specific+non-specific binding) are plotted as a function of thelogarithm of the molar concentration of the competitor (i.e., test orreference compound). Non-linear regression of the normalized (i.e.,percent radioligand binding compared to that observed in the absence oftest or reference compound) raw data is performed in Prism 4.0 (GraphPadSoftware) using the built-in three parameter logistic model describingligand competition binding to radioligand-labeled sites:

y=bottom+[(top-bottom)/(1+10×−log IC₅₀)]

where bottom equals the residual radioligand binding measured in thepresence of 10 μM reference compound (i.e., non-specific binding) andtop equals the total radioligand binding observed in the absence ofcompetitor. The log IC₅₀ (i.e., the log of the ligand concentration thatreduces radioligand binding by 50%) is thus estimated from the data andused to obtain the Ki by applying the Cheng-Prusoff approximation:

Ki=IC₅₀/(1+[ligand]/KD)

where [ligand] equals the assay radioligand concentration and KD equalsthe affinity constant of the radioligand for the target receptor.

Compounds of the disclosure are also screened at a single concentrationof 10 μM using the same method described for the Radiolabel BindingStudies for Serotonin 5HT₇ receptors to determine the percent inhibitionof [³H]LSD binding.

Radiolabel Binding Studies for Serotonin 5-HT7 Receptors, Method 2:

A solution of the compound of the disclosure to be tested is prepared asa 1-mg/ml stock in Assay Buffer or DMSO according to its solubility. Asimilar stock of the reference compound chlorpromazine is also preparedas a positive control. Eleven dilutions (5× assay concentration) of thecompound of the disclosure and chlorpromazine are prepared in the AssayBuffer by serial dilution to yield final corresponding assayconcentrations ranging from 10 pM to 10 μM.

A stock concentration of 5 nM [³H]-5-Hydroxytryptamine ([³H]-5HT) isprepared in 50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EDTA, pH 7.4 (AssayBuffer). Aliquots (50 μl) of radioligand are dispensed into the wells ofa 96-well plate containing 100 μl of Assay Buffer. Duplicate 50-μlaliquots of the compound of the disclosure test and chlorpromazinepositive control reference compound serial dilations are added.

Membrane fractions of cells expressing recombinant 5HT₇ receptors (50μL) are dispensed into each well. The membranes are prepared from stablytransfected cell lines expressing 5HT₇ receptors cultured on 10-cmplates by harvesting PBS-rinsed monolayers, resuspending and lysing inchilled, hypotonic 50 mM Tris-HCl, pH 7.4, centrifuging at 20,000×g,decanting the supernatant and storing at −80° C.; the membranepreparations are resuspended in 3 ml of chilled Assay Buffer andhomogenized by several passages through a 26 gauge needle before usingin the assay.

The 250-μl reactions are incubated at room temperature for 1.5 hours,then harvested by rapid filtration onto 0.3% polyethyleneimine-treated,96-well filter mats using a 96-well Filtermate harvester. Four rapid500-μl washes are performed with chilled Assay Buffer to reducenon-specific binding. The filter mats are dried, then scintillant isadded to the filters and the radioactivity retained on the filters iscounted in a Microbeta scintillation counter.

Raw data (dpm) representing total radioligand binding (i.e.,specific+non-specific binding) are plotted as a function of thelogarithm of the molar concentration of the competitor (i.e., test orreference compound). Non-linear regression of the normalized (i.e.,percent radioligand binding compared to that observed in the absence oftest or reference compound) raw data is performed in Prism 4.0 (GraphPadSoftware) using the built-in three parameter logistic model describingligand competition binding to radioligand-labeled sites:

y=bottom+[(top-bottom)/(1+10×−log IC₅₀)]

where bottom equals the residual radioligand binding measured in thepresence of 10 μM reference compound (i.e., non-specific binding) andtop equals the total radioligand binding observed in the absence ofcompetitor. The log IC₅₀ (i.e., the log of the ligand concentration thatreduces radioligand binding by 50%) is thus estimated from the data andused to obtain the Ki by applying the Cheng-Prusoff approximation:

Ki=IC₅₀/(1+[ligand]/KD)

where [ligand] equals the assay radioligand concentration and KD equalsthe affinity constant of the radioligand for the target receptor.

Compounds of the disclosure are also screened at a single concentrationof 10 μM using the same method described for the Radiolabel BindingStudies for Serotonin 5HT₇ receptors to determine the percent inhibitionof [³H]-5HT binding.

Results for representative compounds according to the present inventionare listed in Table 11.

TABLE 11 Radiolabel Binding Studies for Serotonin 5HT₇ receptors resultsfor exemplary compounds of the disclosure 5-HT₇ Entry Structure IC₅₀(nM) 1

 64 2

277 3

268 4

179 5

104 6

44.5% @ 10 μM 7

 8.9 8

48.9% @ 10 μM 9

26.3% @ 10 μM 10

151 11

911 12

24.5% @ 10 μM 13

227 14

39.8% @ 10 μM 15

130 16

160 N.D. = not determined

Functional Serotonin 5HT₇ Assay, Method 1:

Cell lines stably expressing human 5HT₇ receptors are seeded in 96-well,poly-L-lysine-coated plates 48 hours prior to the assay (40,000 cellsper well) in Dulbecco's Modified Eagle Medium (DMEM) containing 5%dialyzed serum. Twenty hours prior to the assay, the medium is changedto serum-free DMEM. On the day of the assay, the DMEM is washed andreplaced with 30 d of assay buffer (IX Krebs-Ringer bicarbonate glucosebuffer, 0.75 mM IBMX, pH 7.4). A 10-min pre-incubation is performed in a37-degree centigrade, humidified incubator. Then, the cells arestimulated by addition of 30 μl of 2× dilutions of compounds of thedisclosure or chlorpromazine (final concentrations ranging from 0.1 nMto 10 μM, each concentration assayed in triplicate). A positive control(100 μM forskolin) is also included. Accumulation of cAMP is allowed tocontinue for 15 min, after which the buffer is removed and the cells arelysed with Cell Lysis Buffer (CatchPoint cAMP Assay Kit, MolecularDevices). Next, the lysates are transferred to 96-well, glass-bottomplates coated with goat anti-rabbit IgG and adsorbed with rabbitanti-cAMP (Molecular Devices). Following a 5 minute incubation,horseradish peroxidase-cAMP conjugate is added (Molecular Devices) and a2-hour incubation is performed at room temperature. Then, after threewashes with Wash Buffer (Molecular Devices), Stoplight Red substrate(Molecular Devices), reconstituted in Substrate Buffer (MolecularDevices) containing freshly-added 1 mM H₂O₂, is added and, after a15-min incubation at room temperature, fluorescence is measured(excitation 510-545 inn, emission 565-625 nm). For each assay, a cAMPcalibration curve is generated and controls without lysate and withoutantibody are included.

For agonist tests, raw data (maximum fluorescence, fluorescence units)for each concentration of the compounds of the disclosure orchlorpromazine are normalized to the basal (vehicle-stimulated)fluorescence (reported as fold increase over basal) and plotted as afunction of the logarithm of the molar concentration of the drug (i.e.,test or reference compound). Non-linear regression of the normalizeddata is performed in Prism 4.0 (GraphPad Software) using the built-inthree parameter logistic model (i.e., sigmoidal concentration-response)describing agonist-stimulated activation of one receptor population:

y=bottom+[(top-bottom)/(1+10×−log EC50)]

where bottom equals the best-fit basal fluorescence and top equals thebest-fit maximal fluorescence stimulated by the compound of thedisclosure or chlorpromazine. The log EC₅₀ (i.e., the log of the drugconcentration that increases fluorescence by 50% of the maximumfluorescence observed for the compound of the disclosure orchlorpromazine is thus estimated from the data, and the EC₅₀ (agonistpotency) is obtained. To obtain an estimate of the relative efficacy ofthe test compound (Rel. Emax), its best-fit top is compared to andexpressed as a ratio of that for the chlorpromazine (Rel. Emax of thereference agonist is 1.00).

To ascertain whether compounds of the disclosure are antagonists, adouble-addition paradigm is employed. First, 30 μl of a compound of thedisclosure (20 μM) is added (10 pM final concentration) and a 15 minuteincubation is performed. Then, 30 μl of chlorpromazine (3×; EC₉₀) isadded (final concentration of agonist is EC30) and cAMP accumulation isallowed to proceed for 15 minutes. The samples are then processed forcAMP measurements as detailed above. Measurements ofchlorpromazine-induced cAMP accumulation are compared to the signalselicited by the chlorpromazine following addition of vehicle instead oftest compound and expressed as a ratio. ‘Hits’ (compounds thatantagonize chlorpromazine-stimulated increases in baseline-normalizedfluorescence by at least 50%) are then characterized by a modifiedSchild analysis.

For modified Schild analysis, a family of chlorpromazineconcentration-response isotherms is generated in the absence andpresence of graded concentrations of test compound (added 15 min priorto reference agonist). Theoretically, compounds that are competitiveantagonists cause a dextral shift of agonist concentration-responseisotherms without reducing the maximum response to agonist (i.e.,surmountable antagonism). However, on occasion, factors such asnon-competitive antagonism, hemiequilibria, and/or receptor reservecause apparent insurnountable antagonism. To account for suchdeviations, we apply the modified Lew-Angus method to ascertainantagonist potency (Christopoulos et al., 1999). Briefly, equieffectiveconcentrations of agonist (concentrations of agonist that elicit aresponse equal to the EC_(25%) of the agonist control curve) are plottedas a function of the compound of the disclosure concentration present inthe wells in which they were measured. Non-linear regression of thebaseline-normalized data is performed in Prism 4.0 using the followingequation:

pEC25%=−log([B]+10-pK)−log c

where EC25% equals the concentration of agonist that elicits a responseequal to 25% of the maximum agonist control curve response and [B]equals the antagonist concentration; K, c, and s are fit parameters. Theparameter s is equal to the Schild slope factor. If s is notsignificantly different from unity, pK equals pKB; otherwise, pA2 iscalculated (pA2=pK/s). The parameter c equals the ratio EC_(25%)/[B].

Functional Efficacy Assay for 5-HT₇ Receptors Method 2:

Functional efficacy of the compounds of the disclosure on 5-HT₇serotonin receptors were measured in a cell based cAMP enzyme fragmentcomplementation assay using the HitHunter cAMP assay (DiscoveRx). Cellsstably expressing human 5HT₇ receptors were plated in 96-well plates at4000 cells/well, 16-20 hours prior to assay in growth media(Ultraculture medium, 2 mM GlutaMax and G418 1 mg/mL. Serial dilutionsof the agonist, 5-Carboxamidotryptamine (5-CT), were prepared in a finalconcentration range of 10 μM to 10 nM. Compounds of the disclosure wereprepared in 3-fold serial dilutions to obtain a final concentrationrange of 10 μM to 0.1 nM. Compounds of the disclosure are tested foragonist activity in the absence of 5-CT and antagonist activity in thepresence of 5-CT. For the cAMP assay, the protocol was followedaccording to the instructions provided by the supplier. Briefly, cellswere incubated with a compound of the disclosure for 30 minutes at 37°C. prior to addition of EC₇₀ concentration of 5-CT. After an additional30 minutes, cAMP antibody/cell lysis solution was added (20 μL/well) andincubated for 60 minutes at room temperature, cAMP XS+EA reagent isadded (20 μL/well) and incubated for 2 hours at room temperature.Luminescence was read on the Envision Multilabel plate reader.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

1.-12. (canceled)
 13. A compound having formula (IVa):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) andR^(1b) are both ethyl; and at least 2 of the group R^(3a), R^(3b),R^(3c), R^(3d), and R^(3e) are hydrogen and 0 to 3 of R^(3a), R^(3b),R^(3c), R^(3d), and R^(3e) are independently selected from the groupconsisting of OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branchedalkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl, C₁₋₆ linearhaloalkoxy, or heterocyclyl.
 14. A composition comprising an effectiveamount of at least one compound according to claim 13, or apharmaceutically acceptable salt thereof.
 15. The composition accordingto claim 14, further comprising at least one excipient.
 16. A method oftreating a disease associated with dysregulation of 5-hydroxytryptaminereceptor 7 activity, said method comprising administering to a subjectan effective amount of at least one compound according to claim 13, or apharmaceutically acceptable salt thereof, to treat the disease.
 17. Themethod of claim 16, wherein the at least one compound is administered ina composition further comprising at least one excipient.
 18. The methodof claim 16, wherein the disease associated with dysregulation of5-hydroxytryptamine receptor 7 activity is: inflammatory bowel disease,circadian rhythm disorder, depression, schizophrenia, neurogenicinflammation, hypertension, peripheral, vascular diseases, migraine,neuropathic pain, peripheral pain, allodynia, thermoregulation disorder,learning disorder, memory disorder, hippocampal signaling disorder,sleep disorder, attention deficit/hyperactivity disorder, anxiety,avoidant personality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, or bipolar disorder.
 19. A compound selected fromthe group consisting of

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim19, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 21. A compositioncomprising an effective amount of at least one compound according toclaim 19, or a pharmaceutically acceptable salt thereof.
 22. Thecomposition according to claim 21, further comprising at least oneexcipient.
 23. A method of treating a disease associated withdysregulation of 5-hydroxytryptamine receptor 7 activity, said methodcomprising administering to a subject an effective amount of at leastone compound according to claim 19, or a pharmaceutically acceptablesalt thereof, to treat the disease.
 24. The method of claim 23, whereinthe at least one compound is administered in a composition furthercomprising at least one excipient.
 25. The method of claim 23, whereinthe disease associated with dysregulation of 5-hydroxytryptaminereceptor 7 activity is: inflammatory bowel disease, circadian rhythmdisorder, depression, schizophrenia, neurogenic inflammation,hypertension, peripheral, vascular diseases, migraine, neuropathic pain,peripheral pain, allodynia, thermoregulation disorder, learningdisorder, memory disorder, hippocampal signaling disorder, sleepdisorder, attention deficit/hyperactivity disorder, anxiety, avoidantpersonality disorder, premature ejaculation, eating disorder,premenstrual syndrome, premenstrual dysphonic disorder, seasonalaffective disorder, or bipolar disorder.